Compounds for the treatment of inflammatory disorders

ABSTRACT

This invention relates to compounds of the Formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, which can be useful for the treatment of diseases or conditions mediated by MMPs, ADAMs, TACE, aggrecanase, TNF- or combinations thereof.

This application is a continuation-in-part of patent application Ser.No. 11/180,863 filed Jul. 13, 2005, which claims priority from U.S.Provisional Application Ser. No. 60/588,502 filed Jul. 16, 2004.

FIELD OF THE INVENTION

This invention relates generally to novel hydantoin derivatives that caninhibit matrix metalloproteinases (MMPs), a disintegrin andmetalloproteases (ADAMS) and/or tumor necrosis factor alpha—convertingenzyme (TACE) and in so doing prevent the release of tumor necrosisfactor alpha (TNF-α), pharmaceutical compositions comprising suchcompounds, and methods of treatment using such compounds.

BACKGROUND OF THE INVENTION

Osteo- and rheumatoid arthritis (OA and RA, respectively) aredestructive diseases of articular cartilage characterized by localizederosion of the cartilage surface. Findings have shown that articularcartilage from the femoral heads of patients with OA, for example, had areduced incorporation of radiolabeled sulfate over controls, suggestingthat there must be an enhanced rate of cartilage degradation in OA(Mankin et al. J. Bone Joint Surg. 52A (1970) 424-434). There are fourclasses of protein degradative enzymes in mammalian cells: serine,cysteine, aspartic and metalloproteases. The available evidence supportsthe belief that it is the metalloproteases that are responsible for thedegradation of the extracellular matrix of articullar cartilage in OAand RA. Increased activities of collagenases and stromelysin have beenfound in OA cartilage and the activity correlates with severity of thelesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner etal. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). Inaddition, aggrecanase (a newly identified metalloprotease) has beenidentified that provides the specific cleavage product of proteoglycan,found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 36,1993, 1214-22).

Metalloproteases (MPs) have been implicated as the key enzymes in thedestruction of mammalian cartilage and bone. It can be expected that thepathogenesis of such diseases can be modified in a beneficial manner bythe administration of MP inhibitors (see Wahl et al. Ann. Rep. Med.Chem. 25, 175-184, AP, San Diego, 1990).

MMPs are a family of over 20 different enzymes that are involved in avariety of biological processes important in the uncontrolled breakdownof connective tissue, including proteoglycan and collagen, leading toresorption of the extracellular matrix. This is a feature of manypathological conditions, such as RA and OA, corneal, epidermal orgastric ulceration; tumor metastasis or invasion; periodontal diseaseand bone disease. Normally these catabolic enzymes are tightly regulatedat the level of their synthesis as well as at their level ofextracellular activity through the action of specific inhibitors, suchas alpha-2-macroglobulins and TIMPs (tissue inhibitor of MPs), whichform inactive complexes with the MMP's.

Tumor necrosis factor alpha (TNF-α) is a cell-associated cytokine thatis processed from a 26 kDa precursor form to a 17 kd active form. SeeBlack R. A. “Tumor necrosis factor-alpha converting enzyme” Int JBiochem Cell Biol. 2002 January; 34(1):1-5 and Moss M L, White J M,Lambert M H, Andrews R C. “TACE and other ADAM proteases as targets fordrug discovery” Drug Discov Today. 2001 Apr. 1; 6(8):417-426, each ofwhich is incorporated by reference herein.

TNF-α has been shown to play a pivotal role in immune and inflammatoryresponses. Inappropriate or over-expression of TNF-α is a hallmark of anumber of diseases, including RA, Crohn's disease, multiple sclerosis,psoriasis and sepsis. Inhibition of TNF-α production has been shown tobe beneficial in many preclinical models of inflammatory disease, makinginhibition of TNF-α production or signaling an appealing target for thedevelopment of novel anti-inflammatory drugs.

TNF-α is a primary mediator in humans and animals of inflammation, feverand acute phase responses, similar to those observed during acuteinfection and shock. Excess TNF-α has been shown to be lethal. Blockingthe effects of TNF-α with specific antibodies can be beneficial in avariety of conditions, including autoimmune diseases such as RA (Feldmanet al, Lancet, (1994) 344, 1105), non-insulin dependent diabetesmellitus (Lohmander L. S. et al., Arthritis Rheum. 36 (1993) 1214-22)and Crohn's disease (Macdonald T. et al., Clin. Exp. Immunol. 81 (1990)301).

Compounds that inhibit the production of TNF-α are therefore oftherapeutic importance for the treatment of inflammatory disorders.Recently it has been shown that metalloproteases, such as TACE, arecapable of converting TNF-α from its inactive to active form (Gearing etal Nature, 1994, 370, 555). Since excessive TNF-α production has beennoted in several disease conditions also characterized by MMP-mediatedtissue degradation, compounds which inhibit both MMPs and TNF-αproduction may also have a particular advantage in diseases where bothmechanisms are involved.

One approach to inhibiting the harmful effects of TNF-α is to inhibitthe enzyme, TACE before it can process TNF-α to its soluble form. TACEis a member of the ADAM family of type I membrane proteins and mediatesthe ectodomain shedding of various membrane-anchored signaling andadhesion proteins. TACE has become increasingly important in the studyof several diseases, including inflammatory disease, because of its rolein cleaving TNF-α from its “stalk” sequence and thus releasing thesoluble form of the TNF-α protein (Black R. A. Int. J Biochem Cell Biol.2002 34, 1-5).

There are numerous patents and publications which disclose hydroxamate,sulphonamide, hydantoin, carboxylate and/or lactam based MMP inhibitors.

U.S. Pat. Nos. 6,677,355 and 6,534,491 (B2), describe compounds that arehydroxamic acid derivatives and MMP inhibitors.

U.S. Pat. No. 6,495,565 discloses lactam derivatives that are potentialinhibitors of MMPs and/or TNF-α.

PCT Publications WO2002/074750, WO2002/096426, WO20040067996,WO2004012663, WO200274750 and WO2004024721 disclose hydantoinderivatives that are potential inhibitors of MMPs.

PCT Publications WO2004024698 and WO2004024715 disclose sulphonamidederivatives that are potential inhibitors of MMPs.

PCT Publications WO2004056766, WO2003053940 and WO2003053941 alsodescribe potential inhibitors of TACE and MMPs.

There is a need in the art for inhibitors of MMPs, ADAMs, TACE, andTNF-α, which can be useful as anti-inflammatory compounds and cartilageprotecting therapeutics. The inhibition of TNF-α, TACE and or other MMPscan prevent the degradation of cartilage by these enzymes, therebyalleviating the pathological conditions of OA and RA as well as manyother auto-immune diseases.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides a novel class ofcompounds as inhibitors of TACE, the production of TNF-α, MMPs, ADAMs orany combination thereof, methods of preparing such compounds,pharmaceutical compositions comprising one or more such compounds,methods of preparing pharmaceutical formulations comprising one or moresuch compounds, and methods of treatment, prevention, inhibition oramelioration of one or more diseases associated with TACE, TNF-α, MMPs,ADAMs or any combination thereof using such compounds or pharmaceuticalcompositions.

In one embodiment, the present application discloses a compound havingthe general structure shown in formula (I):

or a pharmaceutically acceptable salt, solvate, ester, or isomerthereof, wherein:

X is selected from the group consisting of —S—, —C(R⁴)₂— or —N(R⁴)—;

T is selected from the group consisting of H (with U and V beingabsent), alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylaryl, and arylalkyl, said aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylaryl and arylalkyl being optionally fused with one ormore moieties selected from the group consisting of aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of anyof the aforementioned alkyl, alkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylaryl and arylalkyl groups of T is unsubstituted oroptionally independently substituted with one to four R¹⁰ moieties whichcan be the same or different, each R¹⁰ moiety being independentlyselected from the group of R¹⁰ moieties below;

U is absent or present, and if present U is selected from the groupconsisting of a covalent bond, —N(R⁴)—, —N(R⁴)C(R⁴)₂—, —N(R⁴)C(O)—, —O—,—N(R⁴)S(O)₂—, —N(R⁴)C(O)N(R⁴)—, and —N(R⁴)C(S)N(R⁴)—;

V is absent or present, and if present V is selected from the groupconsisting of alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, saidaryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkylbeing optionally fused with one or more moieties selected from the groupconsisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl andarylalkyl, wherein each of any of the aforementioned alkyl, aryl,heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionallyindependently substituted with one to four R¹⁰ moieties which can be thesame or different, each R¹⁰ moiety being independently selected from thegroup of R¹⁰ moieties below;

Y is absent or present, and if present Y is selected from the groupconsisting of a covalent bond, —(C(R⁴)₂)_(n)—, —N(R⁴)—, —C(O)N(R⁴)—,—N(R⁴)C(O)—, —N(R⁴)C(O)N(R⁴)—, —S(O)₂N(R⁴)—, —N(R⁴)—S(O)₂, —O—, —S—,—C(O)—, —S(O)—, and —S(O)₂—;

Z is absent or present, and if present Z is selected from the groupconsisting of a covalent bond, —(C(R⁴)₂)_(n)—, —N(R⁴)—, —C(O)N(R⁴)—,—N(R⁴)C(O)—, —N(R⁴)C(O)N(R⁴)—, —S(O)₂N(R⁴)—, —N(R⁴)—S(O)₂—, —O—, —S—,—C(O)—, —S(O)—, and —S(O)₂—;

n is 1 to 3;

R¹ is selected from the group consisting of H, —OR⁴, halogen, alkyl,fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryland arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl,heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl groups of R¹ isunsubstituted or optionally independently substituted with one to fourR²⁰ moieties which can be the same or different, each R²⁰ moiety beingindependently selected from the group of R²⁰ moieties below, with theproviso that when Y is present and Y is N, S or O, then R¹ is nothalogen;

R² is selected from the group consisting of H, —OR⁴, halogen, alkyl,fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryland arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl,heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl groups of R² isunsubstituted or optionally independently substituted with one to fourR²⁰ moieties which can be the same or different, each R²⁰ moiety beingindependently selected from the group of R²⁰ moieties below, with theproviso that when Z is present and Z is N, S or O, then R² is nothalogen;

each R⁴ is the same or different and is independently selected from thegroup consisting of H and alkyl;

R¹⁰ is selected from the group consisting of —OR⁴, —N(R⁴)₂, —S(O)—,—S(O)₂—, —N(R⁴)S(O)₂—, —S(O)₂N(R⁴)—, —O(fluoroalkyl), halogen, alkyl,fluoroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl andarylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylaryl and arylalkyl groups of R¹⁰ isunsubstituted or optionally independently substituted with one to fourR³⁰ moieties which can be the same or different, each R³⁰ moiety beingindependently selected from the group of R³⁰ moieties below;

R²⁰ is selected from the group consisting of halogen, alkyl,fluoroalkyl; and

R³⁰ is selected from the group consisting of halogen, alkyl, andfluoroalkyl.

The compounds of Formula I can be useful as inhibitors of TACE and maybe useful in the treatment and prevention of diseases associated withTACE, TNF-α, MMPs, ADAMs or any combination thereof.

DETAILED DESCRIPTION OF THE INVENTION

In its several embodiments, the present invention provides a novel classof inhibitors of TACE, the production of TNF-α, MMPs, ADAMs or anycombination thereof, pharmaceutical compositions containing one or moreof the compounds, methods of preparing pharmaceutical formulationscomprising one or more such compounds, and methods of treatment,prevention or amelioration of one or more of the symptoms ofinflammation.

In one embodiment, the present invention provides compounds which arerepresented by structural Formula (I) above or a pharmaceuticallyacceptable salt, solvate, ester or isomer thereof, wherein the variousmoieties are as described above.

In another embodiment, the isomer referred to the in the precedingparagraph is a stereoisomer.

In one embodiment, T is alkyl or aryl; X is —C(R⁴)₂—; Y is absent; Z isabsent or present; R² is selected from the group consisting of H,halogen and alkyl; and if Z is present Z is —O—.

In another embodiment, T is alkyl or aryl; X is —C(R⁴)₂—; Y is absent; Zis absent or present, and if present Z is —O—; and R² is selected fromthe group consisting of alkylaryl and alkylheteroaryl.

In another embodiment, T is alkyl or aryl; X is —N(R⁴)—; Y is absent; Zis absent or present; R² is selected from the group consisting of H,halogen and alkyl; and if Z is present Z is —O—.

In another embodiment, X is —CH₂— or —N(R⁴)—.

In yet another embodiment, X is —CH₂—.

In still another embodiment, X is —N(R⁴)—.

In another embodiment, R⁴ is H.

In another embodiment, T is alkyl.

In yet another embodiment, T is —CH₃.

In still another embodiment, T is aryl and said aryl is unsubstituted oroptionally independently substituted with one to five R¹⁰ moieties whichcan be the same or different, each R¹⁰ moiety being independentlyselected from the group of R¹⁰ moieties.

In another embodiment, R¹⁰ is halogen.

In yet another embodiment, R¹⁰ is heteroaryl.

In still another embodiment, R¹⁰ is aryl.

In an embodiment U selected from the group consisting of a covalentbond, —N(R⁴)—, —N(R⁴)C(O)—, and —N(R⁴)S(O)₂—.

In yet another embodiment U is a covalent bond.

In still another embodiment U is —N(R⁴)—.

In yet still another embodiment, U is —N(R⁴)C(O)—.

In another embodiment, V is selected from the group consisting of aryl,heteroaryl, heterocyclyl and cycloalkyl, said aryl, heteroaryl,heterocyclyl, and cycloalkyl being optionally fused with one or moremoieties selected from the group consisting of aryl, heteroaryl,heterocyclyl, or cycloalkyl, wherein each of any of said aryl,heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionallyindependently substituted with one to four R¹⁰ moieties which can be thesame or different, each R¹⁰ moiety being independently selected from thegroup of R¹⁰ moieties.

In another embodiment, Y is selected from the group consisting of acovalent bond, —(C(R⁴)₂)_(n)—, —C(O)— and —O—.

In yet another embodiment, Y is —O—.

In still another embodiment, Y is —(C(R⁴)₂)_(n)—.

In yet still another embodiment, Y is —C(O)—.

In another embodiment, Y is a covalent bond.

In an embodiment, R¹ is selected from the group consisting of —OR⁴, H,alkyl, fluoroalkyl, alkylaryl, halogen, and heteroaryl.

In another embodiment, R¹ is H.

In yet another embodiment, R¹ is alkylaryl.

In still another embodiment, R¹ is alkyl.

In yet still another embodiment, R¹ is fluoroalkyl.

In a further embodiment, R¹ is halogen.

In another embodiment, R¹ is —OR⁴.

In another embodiment, where R¹ is —OR⁴, R⁴ is —CH₂C≡CCH₃.

In another embodiment, where R¹ is —OR⁴, R⁴ is —CH₂C≡CCH₂OH.

In another embodiment, where R¹ is —OR⁴, R⁴ is

In another embodiment, the alkyl is —CH₃.

In still another embodiment, the alkyl is —CH₂CH₃.

In another embodiment, in formula (I), T, U, and V are taken together toform

and R¹ is selected from the group consisting of F, Cl, OH, —OCH₂C≡CCH₃,—OCH₂C≡CCH₂OH, —OCH₃, and

In another embodiment, in formula (I), T, U, and V are taken together toform

and R¹ is selected from the group consisting of F, Cl, OH, —OCH₂C≡CCH₃,—OCH₂C≡CCH₂OH, —OCH₃, and

In another embodiment, in formula (I), T, U, and V are taken together toform

and R¹ is selected from the group consisting of F, Cl, OH,—OCH₂C≡CCH₃—OCH₂C≡CCH₂OH, —OCH₃, and

In another embodiment, in formula (I), T, U, and V are taken together toform

and R¹ is selected from the group consisting of F, Cl, OH, —OCH₂C≡CCH₃,—OCH₂C≡CCH₂OH, —OCH₃, and

In another embodiment, in formula (I), T, U, and V are taken together toform

and R¹ is selected from the group consisting of F, Cl, OH, —OCH₂C≡CCH₃,—OCH₂C≡CCH₂OH, —OCH₃, and

In another embodiment, in formula (I), T, U, and V are taken together toform

and R² is selected from the group consisting of F, Cl, OH, —OCH₂C≡CCH₃,—OCH₂C≡CCH₂OH, —OCH₃, and

In another embodiment, in formula (I), T, U, and V are taken together toform

and R² is selected from the group consisting of F, Cl, OH, —OCH₂C≡CCH₃,—OCH₂C≡CCH₂OH, —OCH₃, and

In another embodiment, in formula (I), T, U, and V are taken together toform

and R² is selected from the group consisting of F, Cl, OH, —OCH₂C≡CCH₃,—OCH₂C≡CCH₂OH, —OCH₃, and

In another embodiment, in formula (I), T, U, and V are taken together toform

and R² is selected from the group consisting of F, Cl, OH, —OCH₂C≡CCH₃,—OCH₂C≡CCH₂OH, —OCH₃, and

In another embodiment, in formula (i), T, U, and V are taken together toform

and R² is selected from the group consisting of F, Cl, OH, —OCH₂C≡CCH₃,—OCH₂C≡CCH₂OH, —OCH₃, and

In another embodiment, the fluoroalkyl is —CH₂CF₃.

In an embodiment, halogen is selected from the group consisting of —Br,—Cl and —F.

In another embodiment, R⁴ is —CH₃.

In yet another embodiment, alkyl of R¹ is substituted with one to fourR²⁰ moieties which can be the same or different, each R²⁰ moiety beingindependently selected from the group of R²⁰ moieties.

In another embodiment, R²⁰ is aryl.

In another embodiment, Z is selected from the group consisting of acovalent bond, —N(R⁴)—, —(C(R⁴)₂)_(n)—, —C(O)— and —O—.

In yet another embodiment, Z is —O—.

In still another embodiment, Z is a covalent bond.

In yet still another embodiment, Z is —N(R⁴)—.

In a further embodiment, Z is —C(O)—.

In another embodiment, R⁴ is alkyl.

In another embodiment, R² is selected from the group consisting of —OR⁴,H, alkyl, fluoroalkyl, alkylaryl, halogen, and heteroaryl.

In another embodiment wherein R² is —OR⁴, R⁴ is —CH₂C≡CCH₃.

In another embodiment wherein R² is —OR⁴, R⁴ is —CH₂C≡CCH₂OH.

In another embodiment wherein R² is —OR⁴, R⁴ is

In yet another embodiment, R² is hydrogen.

In still another embodiment, R² is alkyl.

In yet still another embodiment, R² is alkylaryl.

In yet further embodiment, R² is fluoroalkyl.

In another embodiment, R² is —CH₂CF₃.

In yet another embodiment, R² is halogen.

In another embodiment, R² is heteroaryl.

In another embodiment, R⁴ is —CH₃.

Another embodiment of the invention discloses the following compoundsshown in Table A below.

TABLE A Structures

Enantiomer A

Enantiomer B

Enantiomer A

Enantiomer B

Enantiomer A

Enantiomer B

Another embodiment of the invention discloses the preferred compoundsshown in Table B below:

TABLE B Structure

Enantiomer A

Enantiomer B

Enantiomer B

Another embodiment of the invention discloses the more preferredcompounds shown in Table C below.

TABLE C Structure

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. The alkyl group may besubstituted by one or more substituents which may be the same ordifferent, each substituent being independently selected from the groupconsisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy,alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, carboxy and—C(O)O-alkyl. Non-limiting examples of suitable alkyl groups includemethyl, ethyl, n-propyl, isopropyl and t-butyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkenyl groups includeethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyland decenyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term “substitutedalkynyl” means that the alkynyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of alkyl, aryl andcycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. Non-limitingexamples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, pyridone (including N-substituted pyridones),isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

“Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl andalkyl are as previously described. Preferred aralkyls comprise a loweralkyl group. Non-limiting examples of suitable aralkyl groups includebenzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parentmoiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are aspreviously described. Preferred alkylaryls comprise a lower alkyl group.Non-limiting example of a suitable alkylaryl group is tolyl. The bond tothe parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like, as well aspartially saturated species such as, for example, indanyl,tetrahydronaphthyl and the like.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine and bromine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl,heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl),G₁G₂N—, G₁G₂N-alkyl-, G₁G₂NC(O)—, G₁G₂NSO₂— and —SO₂NG₁G₂, wherein G₁and G₂ can be the same or different and are independently selected fromthe group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl.“Ring system substituent” may also mean a single moiety whichsimultaneously replaces two available hydrogens on two adjacent carbonatoms (one H on each carbon) on a ring system. Examples of such moietyare methylene dioxy, ethylenedioxy, —C(CH₃)₂— and the like which formmoieties such as, for example:

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising about 3 to about 10 ring atoms, preferably about5 to about 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur, alone or in combination. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Preferred heterocyclyls containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom respectively is present as a ring atom. Any —NH in a heterocyclylring may exist protected such as, for example, as an —N(Boc), —N(CBz),—N(Tos) group and the like; such protections are also considered part ofthis invention. The heterocyclyl can be optionally substituted by one ormore “ring system substituents” which may be the same or different, andare as defined herein. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, lactam, lactone, and the like.

It should be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

“Alkynylalkyl” means an alkynyl-alkyl-group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl-group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

The term “isolated” or “in isolated form” for a compound refers to thephysical state of said compound after being isolated from a syntheticprocess or natural source or combination thereof. The term “purified” or“in purified form” for a compound refers to the physical state of saidcompound after being obtained from a purification process or processesdescribed herein or well known to the skilled artisan, in sufficientpurity to be characterizable by standard analytical techniques describedherein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of Formula I or a salt and/or solvatethereof. A discussion of prodrugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, (1987)Edward B. Roche, ed., American Pharmaceutical Association and PergamonPress, both of which are incorporated herein by reference thereto. Theterm “prodrug” means a compound (e.g, a drug precursor) that istransformed in vivo to yield a compound of Formula (I) or apharmaceutically acceptable salt, hydrate or solvate of the compound.The transformation may occur by various mechanisms (e.g., by metabolicor chemical processes), such as, for example, through hydrolysis inblood. A discussion of the use of prodrugs is provided by T. Higuchi andW. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987.

For example, if a compound of Formula (I) or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C1-C2)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula (I) incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄)alkyl and Y³ is (C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-Nordi-N,N-(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N-(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting TACE, the production of TNF-α, MMPs, ADAMS orany combination thereof and thus producing the desired therapeutic,ameliorative, inhibitory or preventative effect.

The compounds of Formula I can form salts which are also within thescope of this invention. Reference to a compound of Formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula I may be formed, for example, by reacting a compound ofFormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Compounds of Formula I, and salts, solvates and prodrugs thereof, mayexist in their tautomeric form (for example, as an amide or iminoether). All such tautomeric forms are contemplated herein as part of thepresent invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates and prodrugs of the compounds as well as the salts and solvatesof the prodrugs), such as those which may exist due to asymmetriccarbons on various substituents, including enantiomeric forms (which mayexist even in the absence of asymmetric carbons), rotameric forms,atropisomers, and diastereomeric forms, are contemplated within thescope of this invention, as are positional isomers (such as, forexample, 4-pyridyl and 3-pyridyl). Individual stereoisomers of thecompounds of the invention may, for example, be substantially free ofother isomers, or may be admixed, for example, as racemates or with allother, or other selected, stereoisomers. The chiral centers of thepresent invention can have the S or R configuration as defined by theIUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”“prodrug” and the like, is intended to equally apply to the salt,solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers,positional isomers, racemates or prodrugs of the inventive compounds.

Polymorphic forms of the compounds of Formula I, and of the salts,solvates and prodrugs of the compounds of Formula I, are intended to beincluded in the present invention.

The compounds according to the invention have pharmacologicalproperties; in particular, the compounds of Formula I can be inhibitorsof TACE, TNF-α and/or MMP activity.

In one aspect, the invention provides a pharmaceutical compositioncomprising as an active ingredient at least one compound of formula (I).

In another aspect, the invention provides a pharmaceutical compositionof formula (I) additionally comprising at least one pharmaceuticallyacceptable carrier.

In another aspect, the invention provides a method of treating disordersassociated with TACE, TNF-α, MMPs, ADAMs or any combination thereof,said method comprising administering to a patient in need of suchtreatment a pharmaceutical composition which comprises therapeuticallyeffective amounts of at least one compound of formula (I).

In another aspect, the invention provides a use of a compound of formula(I) for the manufacture of a medicament to treat disorders associatedwith TACE, TNF-α, MMPs, ADAMs or any combination thereof.

The compounds of Formula I can have anti-inflammatory activity and/orimmunomodulatory activity and can be useful in the treatment of diseasesincluding but not limited to septic shock, haemodynamic shock, sepsissyndrome, post ischaemic reperfusion injury, malaria, mycobacterialinfection, meningitis, psoriasis, congestive heart failure, fibroticdiseases, cachexia, graft rejection, cancers such as cutaneous T-celllymphoma, diseases involving angiogenesis, autoimmune diseases, skininflammatory diseases, inflammatory bowel diseases such as Crohn'sdisease and colitis, OA and RA, ankylosing spondylitis, psoriaticarthritis, adult Still's disease, ureitis, Wegener's granulomatosis,Behcehe disease, Sjogren's syndrome, sarcoidosis, polymyositis,dermatomyositis, multiple sclerosis, sciatica, complex regional painsyndrome, radiation damage, hyperoxic alveolar injury, periodontaldisease, HIV, non-insulin dependent diabetes mellitus, systemic lupuserythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis,bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis,renal ischemia, myocardial infarction, cerebral stroke, cerebralischemia, nephritis, hepatitis, glomerulonephritis, cryptogenicfibrosing aveolitis, psoriasis, transplant rejection, atopic dermatitis,vasculitis, allergy, seasonal allergic rhinitis, reversible airwayobstruction, adult respiratory distress syndrome, asthma, chronicobstructive pulmonary disease (COPD) and/or bronchitis. It iscontemplated that a compound of this invention may be useful in treatingone or more of the diseases listed.

In another aspect, the invention provides a method of preparing apharmaceutical composition for treating the disorders associated withTACE, TNF-α, MMPs, ADAMs or any combination thereof, said methodcomprising bringing into intimate contact at least one compound offormula (I) and at least one pharmaceutically acceptable carrier.

In another aspect, the invention provides a compound of formula (I)exhibiting TACE, TNF-α, MMPs, ADAMs or any combination thereofinhibitory activity, including enantiomers, stereoisomers and tautomersof said compound, and pharmaceutically acceptable salts, esters, orsolvates of said compound, said compound being selected from thecompounds of structures listed in Table A set forth above.

In another aspect, the invention provides a pharmaceutical compositionfor treating disorders associated with TACE, TNF-α, MMP, ADAM or anycombination thereof in a subject comprising, administering to thesubject in need of such treatment a therapeutically effective amount ofat least one compound of formula (I) or a pharmaceutically acceptablesalt, solvate, ester or isomer thereof.

In another aspect, the invention provides a compound of formula (I) inpurified form.

In another aspect, the invention provides a method of treating acondition or disease mediated by TACE, MMPs, TNF-α, aggrecanase, or anycombination thereof in a subject comprising: administering to thesubject in need of such treatment a therapeutically effective amount ofat least one compound of formula (I) or a pharmaceutically acceptablesalt, solvate, ester or isomer thereof.

In another aspect, the invention provides a method of treating acondition or disease selected from the group consisting of rheumatoidarthritis, osteoarthritis, periodontitis, gingivitis, cornealulceration, solid tumor growth and tumor invasion by secondarymetastases, neovascular glaucoma, inflammatory bowel disease, multiplesclerosis and psoriasis in a subject, comprising: administering to thesubject in need of such treatment a therapeutically effective amount ofat least one compound of formula (I) or a pharmaceutically acceptablesalt, solvate, ester, or isomer thereof.

In another aspect, the invention provides a method of treating acondition or disease selected from the group consisting of fever,cardiovascular conditions, hemorrhage, coagulation, cachexia, anorexia,alcoholism, acute phase response, acute infection, shock, graft versushost reaction, autoimmune disease and HIV infection in a subjectcomprising administering to the subject in need of such treatment atherapeutically effective amount of at least one compound of formula (I)or a pharmaceutically acceptable salt, solvate, ester, or isomerthereof.

In another aspect, the invention provides a method of treating acondition or disease selected from the group consisting of septic shock,haemodynamic shock, sepsis syndrome, post ischaemic reperfusion injury,malaria, mycobacterial infection, meningitis, psoriasis, congestiveheart failure, fibrotic diseases, cachexia, graft rejection, cancerssuch as cutaneous T-cell lymphoma, diseases involving angiogenesis,autoimmune diseases, skin inflammatory diseases, inflammatory boweldiseases such as Crohn's disease and colitis, osteo and rheumatoidarthritis, ankylosing spondylitis, psoriatic arthritis, adult Still'sdisease, ureitis, Wegener's granulomatosis, Behcehe disease, Sjogren'ssyndrome, sarcoidosis, polymyositis, dermatomyositis, multiplesclerosis, sciatica, complex regional pain syndrome, radiation damage,hyperoxic alveolar injury, periodontal disease, HIV, non-insulindependent diabetes mellitus, systemic lupus erythematosus, glaucoma,sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia,retinal disease, scleroderma, osteoporosis, renal ischemia, myocardialinfarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis,glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis,transplant rejection, atopic dermatitis, vasculitis, allergy, seasonalallergic rhinitis, reversible airway obstruction, adult respiratorydistress syndrome, asthma, chronic obstructive pulmonary disease (COPD)and bronchitis in a subject comprising administering to the subject inneed of such treatment a therapeutically effective amount of at leastone compound of formula (I) or a pharmaceutically acceptable salt,solvate, ester or isomer thereof.

In another aspect, the invention provides a method of treating acondition or disease associated with COPD, comprising: administering tothe subject in need of such treatment a therapeutically effective amountof at least one compound of formula (I) or a pharmaceutically acceptablesalt, solvate, ester, or isomer thereof.

In another aspect, the invention provides a method of treating acondition or disease associated with rheumatoid arthritis, comprising:administering to the subject in need of such treatment a therapeuticallyeffective amount of at least one compound of formula (I) or apharmaceutically acceptable salt, solvate, ester or isomer thereof.

In another aspect, the invention provides a method of treating acondition or disease associated with Crohn's disease, comprising:administering to the subject in need of such treatment a therapeuticallyeffective amount of at least one compound of formula (I) or apharmaceutically acceptable salt, solvate, ester or isomer thereof.

In another aspect, the invention provides a method of treating acondition or disease associated with psoriasis, comprising:administering to the subject in need of such treatment a therapeuticallyeffective amount of at least one compound of formula (I) or apharmaceutically acceptable salt, solvate, ester, or isomer thereof.

In another aspect, the invention provides a method of treating acondition or disease associated with ankylosing spondylitis, comprising:administering to the subject in need of such treatment a therapeuticallyeffective amount of at least one compound of formula (I) or apharmaceutically acceptable salt, solvate, ester, or isomer thereof.

In another aspect, the invention provides a method of treating acondition or disease associated with sciatica, comprising: administeringto the subject in need of such treatment a therapeutically effectiveamount of at least one compound of formula (I) or a pharmaceuticallyacceptable salt, solvate, ester or isomer thereof.

In another aspect, the invention provides a method of treating acondition or disease associated with complex regional pain syndrome,comprising: administering to the subject in need of such treatment atherapeutically effective amount of at least one compound of formula (I)or a pharmaceutically acceptable salt, ester, solvate or isomer thereof.

In another aspect, the invention provides a method of treating acondition or disease associated with psoriatic arthritis, comprising:administering to the subject in need of such treatment a therapeuticallyeffective amount of at least one compound of formula (I) or apharmaceutically acceptable salt, solvate, ester or isomer thereof.

In another aspect, the invention provides a method of treating acondition or disease associated with multiple sclerosis, comprising:administering to the subject in need of such treatment a therapeuticallyeffective amount of at least one compound of formula (I) or apharmaceutically acceptable salt, solvate, ester or isomer thereof, incombination with a compound selected from the group consisting ofAvonex®, Betaseron, Copaxone or other compounds indicated for thetreatment of multiple sclerosis.

Additionally, a compound of the present invention may be co-administeredor used in combination with disease-modifying antirheumatic drugs(DMARDS) such as methotrexate, azathioprine, leflunomide,pencillinamine, gold salts, mycophenolate mofetil, cyclophosphamide andother similar drugs. They may also be co-administered with or used incombination with non-steroidal anti-inflammatory drugs (NSAIDs) such aspiroxicam, naproxen, indomethacin, ibuprofen and the like;cycloxygenase-2 selective (COX-2) inhibitors such as Vioxx® andCelebrex®; immunosuppressives such as steroids, cyclosporin, Tacrolimus,rapamycin and the like; biological response modifiers (BRMs) such asEnbrel®, Remicade®, IL-1 antagonists, anti-CD40, anti-CD28, IL-10,anti-adhesion molecules and the like; and other anti-inflammatory agentssuch as p38 kinase inhibitors, PDE4 inhibitors, other chemicallydifferent TACE inhibitors, chemokine receptor antagonists, Thalidomideand other small molecule inhibitors of pro-inflammatory cytokineproduction.

Also, a compound of the present invention may be co-administered or usedin combination with an H1 antagonist for the treatment of seasonalallergic rhinitis and/or asthma. Suitable H1 antagonists may be, forexample, Claritin®, Clarinex®, Allegra®, or Zyrtec®.

In another aspect, the invention provides a method of treating acondition or disease mediated by TACE, MMPs, TNF-α, aggrecanase, or anycombination thereof in a subject comprising: administering to thesubject in need of such treatment a therapeutically effective amount ofat least one compound of formula (I) or a pharmaceutically acceptablesalt, solvate, ester or isomer thereof in combination with atherapeutically effective amount of at least one medicament selectedfrom the group consisting of disease modifying anti-rheumatic drugs(DMARDS), NSAIDs, COX-2 inhibitors, COX-1 inhibitors,immunosuppressives, biological response modifiers (BRMs),anti-inflammatory agents and H1 antagonists.

In another aspect, the invention provides a method of treating acondition or disease selected from the group consisting of rheumatoidarthritis, osteoarthritis, periodontitis, gingivitis, cornealulceration, solid tumor growth and tumor invasion by secondarymetastases, neovascular glaucoma, inflammatory bowel disease, multiplesclerosis and psoriasis in a subject, comprising: administering to thesubject in need of such treatment a therapeutically effective amount ofat least one compound of formula (I) or a pharmaceutically acceptablesalt, solvate, ester or isomer thereof in combination with atherapeutically effective amount of at least one medicament selectedfrom the group consisting of DMARDS, NSAIDs, COX-2 inhibitors, COX-1inhibitors, immunosuppressives, BRMs, anti-inflammatory agents and H1antagonists.

In another aspect, the invention provides a method of treating acondition or disease selected from the group consisting of septic shock,haemodynamic shock, sepsis syndrome, post ischaemic reperfusion injury,malaria, mycobacterial infection, meningitis, psoriasis, congestiveheart failure, fibrotic diseases, cachexia, graft rejection, cancerssuch as cutaneous T-cell lymphoma, diseases involving angiogenesis,autoimmune diseases, skin inflammatory diseases, inflammatory boweldiseases such as Crohn's disease and colitis, osteo and rheumatoidarthritis, ankylosing spondylitis, psoriatic arthritis, adult Still'sdisease, ureitis, Wegener's granulomatosis, Behcehe disease, Sjogren'ssyndrome, sarcoidosis, polymyositis, dermatomyositis, multiplesclerosis, sciatica, complex regional pain syndrome, radiation damage,hyperoxic alveolar injury, periodontal disease, HIV, non-insulindependent diabetes mellitus, systemic lupus erythematosus, glaucoma,sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia,retinal disease, scleroderma, osteoporosis, renal ischemia, myocardialinfarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis,glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis,transplant rejection, atopic dermatitis, vasculitis, allergy, seasonalallergic rhinitis, reversible airway obstruction, adult respiratorydistress syndrome, asthma, chronic obstructive pulmonary disease (COPD)and bronchitis in a subject comprising administering to the subject inneed of such treatment a therapeutically effective amount of at leastone compound of formula (I) or a pharmaceutically acceptable salt,solvate, ester or isomer thereof in combination with a therapeuticallyeffective amount of at least one medicament selected from the groupconsisting of DMARDS, NSAIDs, COX-2 inhibitors, COX-1 inhibitors,immunosuppressives, BRMs, anti-inflammatory agents and H1 antagonists.

In another aspect, the invention provides a method for treating RAcomprising administering a compound of the formula I in combination withcompound selected from the class consisting of a COX-2 inhibitor e.g.Celebrex® or Vioxx®; a COX-1 inhibitor e.g. Feldene®; animmunosuppressive e.g. methotrexate or cyclosporin; a steroid e.g.β-methasone; and anti-TNF-α compound, e.g. Enbrel® or Remicade®; a PDEIV inhibitor, or other classes of compounds indicated for the treatmentof RA.

In another aspect, the invention provides a method for treating multiplesclerosis comprising administering a compound of the formula I incombination with a compound selected from the group consisting ofAvonex®, Betaseron, Copaxone or other compounds indicated for thetreatment of multiple sclerosis.

TACE activity is determined by a kinetic assay measuring the rate ofincrease in fluorescent intensity generated by TACE catalyzed cleavageof an internally quenched peptide substrate (SPDL-3). The purifiedcatalytic domain of recombinant human TACE (rhTACEc, Residue 215 to 477with two mutation (S266A and N452Q) and a 6×His tail) is used in theassay. It is purified from the baculovirus/Hi5 cells expression systemusing affinity chromatography. The substrate SPDL-3 is an internallyquenched peptide(MCA-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Dpa-Arg-NH2), with itssequence derived from the pro-TNFα cleavage site. MCA is(7-Methoxycoumarin-4-yl)acetyl. Dpa isN-3-(2,4-Dinitrophenyl)-L-2,3-diaminopropionyl.

A 50 μl assay mixture contains 20 mM HEPES, pH 7.3, 5 mM CaCl₂, 100 μMZnCl₂, 2% DMSO, 0.04% Methylcellulose, 30 μM SPDL-3, 70 pM rhTACEc and atest compound. RhTACEc is pre-incubated with the testing compound for 90min. at 25° C. Reaction is started by addition of the substrate. Thefluorescent intensity (excitation at 320 nm, emission at 405 nm) wasmeasured every 45 seconds for 30 min. using a fluorospectrometer (GEMINIXS, Molecular Devices). Rate of enzymatic reaction is shown as Units persecond. Effect of a test compound is shown as % of TACE activity in theabsence of the compound.

Useful compounds for TACE inhibitory activity can exhibit K_(i) valuesof less than about 1000 nm, preferably about 0.01 nm to about 1000 nm,more preferably about 0.1 nm to about 100 nm, and most preferably lessthan about 15 nm. The TACE inhibitory activity (Ki values) of somerepresentative compounds of the present invention are listed in the“EXAMPLES” section hereinbelow.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets contain the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipients that are suitable forthe manufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the technique described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets forcontrolled release.

The term pharmaceutical composition is also intended to encompass boththe bulk composition and individual dosage units comprised of more thanone (e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the afore-said “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets, pillsand the like. Similarly, the herein-described method of treating apatient by administering a pharmaceutical composition of the presentinvention is also intended to encompass the administration of theafore-said bulk composition and individual dosage units.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredients is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or a softgelatin capsules where in the active ingredient is mixed with water oran oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellu lose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanthand gum acacia; dispersing or wetting agents may be anaturally-occurring phosphatide, for example, lecithin, or condensationproducts of an alkylene oxide with fatty acids, for examplepolyoxyethylene stearate, or condensation products of ethylene oxidewith long chain aliphatic alcohols, for example,heptadecaethylene-oxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example, polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives, for example,ethyl or n-propyl, p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such assucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, e.g., sweetening, flavoring and coloring agents,may also be present.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsion. The oily phase may be a vegetable oil,e.g., olive oil or arachis oil, or a mineral oil, e.g., liquid paraffinor mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, e.g., soy beans, lecithin, and estersor partial esters derived from fatty acids and hexitol anhydrides, forexample, sorbitan monooleate, and condensation products of the saidpartial esters with ethylene oxide, e.g., polyoxyethylene sorbitanmonooleate. The emulsions may also contain sweetening and flavoringagents.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, e.g., as a solution in 1,3-butane diol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Compounds of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. The compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the invention are employed. (Forpurposes of this application, topical application shall includemouthwashes and gargles.)

The compounds for the present invention can be administered in theintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wellknown to those of ordinary skill in the art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen. Compounds of the present invention may also be delivered as asuppository employing bases such as cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, weight, sex and medical condition of the patient; the severityof the condition to be treated; the route of administration; the renaland hepatic function of the patient; and the particular compound thereofemployed. A physician or veterinarian of ordinary skill can readilydetermine and prescribe the effective amount of the drug required toprevent, counter, arrest or reverse the progress of the condition.Optimal precision in achieving concentration of drug within the rangethat yields efficacy without toxicity requires a regimen based on thekinetics of the drug's availability to target sites. This involves aconsideration of the distribution, equilibrium, and elimination of adrug. Preferably, doses of the compound of Formula I useful in themethod of the present invention range from 0.01 to 1000 mg per day. Morepreferably, dosages range from 0.1 to 1000 mg/day. Most preferably,dosages range from 0.1 to 500 mg/day. For oral administration, thecompositions are preferably provided in the form of tablets containing0.01 to 1000 milligrams of the active ingredient, particularly 0.01,0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. An effective amount of the drugis ordinarily supplied at a dosage level of from about 0.0002 mg/kg toabout 50 mg/kg of body weight per day. The range is more particularlyfrom about 0.001 mg/kg to 1 mg/kg of body weight per day.

Advantageously, the active agent of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in dividend doses of two, three or four time daily.

The amount of active ingredient that may be combined with the carriermaterials to produce single dosage form will vary depending upon thehost treated and the particular mode of administration.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route or administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

The compounds of the invention may be produced by processes known tothose skilled in the art and as shown in the following reaction schemesand in the preparations and examples described below.

EXAMPLES

The following abbreviations are used in the procedures and schemes:

ACN Acetonitrile AcOH Acetic acid Aq Aqueous BOC tert-ButoxycarbonylBOC-ON [2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitril] BOC₂O BOCAnhydride C degrees Celsius CBZCl Benzyl chloroformate DBU1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DEAD Diethylazodicarboxylate (DHQ)2PHAL Hydroquinine 1,4-phthalazinediyl dietherDIAD Diisopropylazodicarboxylate DIPEA Diisopropylethylamine DMAN,N-Dimethylacetamide DMAP 4-Dimethylaminopyridine DME DimethoxyethaneDMF Dimethylformamide DMFDMA N,N-Dimethylformamide dimethylacetal DMPU1,3-Dimethyl-3,4,5,6-tetrahydro-2(1h)-pyrimidinone DMSO Dimethylsulfoxide EDCl 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride EI Electron ionization Eq Equivalents EtOAc Ethyl acetateEtOH Ethanol g grams h. hours ¹H proton HATU N,N,N′,N′-Tetramethyl-O-(7-Azabenzotriazol-1-yl) Uronium hexafluorophosphateHex hexanes HOBT 1-Hydroxybenzotriazole HPLC High pressure liquidchromatography LAH Lithium aluminum hydride LDA Lithium diisopropylamideM Molar mmol milimolar mCPBA meta-Chloroperoxybenzoic acid Me MethylMeCN Acetonitrile MeOH Methanol min Minutes mg Milligrams MHZ MegahertzmL Milliliter MPLC Medium Pressure Liquid Chromatography NMR NuclearMagnetic Resonance MS Mass Spectroscopy NBS N-Bromosuccinimide NMMN-Methylmorpholine NMP 1-methyl-2-pyrrolidone ON Overnight PCCPyridinium Chlorochromate PTLC Preparative thin layer chromatographyPyBrOP Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate PyrPyridine RT Room temperature sgc Silica gel 60 chromatography tBOCtert-Butoxycarbonyl TACE TNF-alpha converting enzyme TEA TriethylamineTFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layerchromatography

NMR spectra were acquired on the following instruments: 400 MHZ NMR(Bruker), 500 MHZ NMR (Bruker), 400 MHz NMR (Varian), 300 MHZ NMR(Varian) using CD₃OD, CDCl₃ or DMSO-d₆ as solvents. LC-MS data wereobtained using a PESciex API 150EX quadropole mass spectrometer usingelectroscopy ionization.

Purification via reverse phase chromatography (Gilson) was accomplishedusing a C18 reverse phase column with a gradient of (0.1% formic acid)5:95 to 90:10 acetonitrile:water, at a flow rate of 14 mL/min. Sampleswere collected using UV detection. Alternatively an ISCO Companion with(0.1% formic acid) 5:95 to 95:5 acetonitrile:water, at a flow rate=10-55mL/min.

Normal phase silica gel chromatography was either accomplished on aBiotage instrument using a 60 Å 12/M, 25/M, or 40/M flash cartridges, oron a Jones Flash Master Personal instrument using Isolute flash SI 5 g,10 g, 20 g, 50 g, or 70 g cartridges.

The compounds of formula (I) may be produced by processes known to thoseskilled in the art and as shown in the following reaction schemes and inthe preparations and examples described below. These preparations andexamples should not be construed to limit the scope of the disclosure.Alternate mechanistic pathways and analogous structures may be apparentto those skilled in the art. Some of the compounds made by theseprocesses are listed in the tables below. All kinds of isomeric forms ofthe compounds are considered to be within the scope of this invention.

SYNTHETIC ROUTES AND EXAMPLES Example 1

General Procedures for Example 1:

In step 1, Compound 1A (either commercially available, or prepared by aprocedure similar to that described by Abdalla, G. M. and Sowell, J. W.Journal of Heterocyclic Chemistry, 1987, 24(2), 297-301) was treatedwith one equivalent of Di-tert-butyl dicarbonate in polar solvent, suchas DMF, for 30 minutes to 12 hours. The solvent was removed and compound1B could be used without further purification or purified by silica gelchromatography.

In step 2, compound 1B was reacted with potassium cyanide and ammoniumcarbonate in appropriated alcohol and water solution, at 50° C. to 90°C., for 5 hours to 48 hours. After cooling down, water was added andcompound 1C could be collected by filtration.

In step 3, compound 1C was stirred with 2 to 20 equivalents of hydrogenchloride in methanol for 5 to 48 hours. After ethyl ether was added,compound 1D could be collected by filtration.

Example 2

Step 1

Compound 2A (Abdalla, G. M. and Sowell, J. W. Journal of HeterocyclicChemistry, 1987, 24(2), 297-301) (Hydrochloride salt, 8.60 g, 45.4mmol), triethyl amine (19.0 mL, 136 mmol), and di-tert-butyl dicarbonate(11.9 g, 54.4 mmol) were stirred in methylene chloride (100 mL) at 25°C. for 16 hours. Saturated aqueous NaHCO₃ (150 mL) was added. Theaqueous layer was extracted with CH₂Cl₂ (100 mL) twice. The organicphase was washed with brine (100 mL) and dried over Na₂SO₄. The solventwas removed by rotary evaporator to give compound 2B which was usedwithout further purification.

Step 2

Compound 2B (9.06 g, 35.8 mmol), KCN (3.49 g, 53.7 mmol), and (NH₄)₂CO₃(12.0 g, 125.2 mmol) were suspended in a mixture of EtOH (35 mL) andwater (35 mL). The solution was stirred at 70° C. for three days. Aftercooling down, water (35 mL) was added. The solid was filtered and washedwith water three times. The solid was dried under vacuum at 40° C. for16 hours to give compound 2C (7.9 g, 68%).

Step 3

Compound 2C (4.0 g) was suspended in methanol (50 mL) and HCl (4M indioxane, 20 mL) was added. The solution was stirred at 25° C. for 3hours. Ethyl ether (50 ml) was added. The solid was filtered, washedwith ethyl ether twice, and dried under vacuum for 12 hours to givecompound 2D (2.7 g, 84%).

The following intermediates were prepared as described in Examples 1 and2.

Example 3

General Procedures for Example 3

In step 1,5-Hydroxy-2-nitro-benzoic acid (compound 3A) was dissolved ina suitable solvent, such as DMF, and reacted with an alkyl chloride oralkyl bromide in the presence of cesium carbonate at room temperaturefor 2 to 16 hours. Water and EtOAc were added. The organic phase waswashed by water 1 to 5 times to remove DMF. The organic phase was washedwith brine, dried, concentrated to give the crude product (compound 3B)which was used without further purification.

In step 2, compound 3B was dissolved in dioxane/water (3:1) and treatedwith lithium hydroxide at room temperature for 3 to 6 hours. Thesolution was made acidic by addition of 1N HCl solution and extractedwith EtOAc. The products (compound 3C) were either used without furtherpurification or purified by chromatography depending on the boilingpoint of the alcohol side products.

In step 3, compound 3C was dissolved in a suitable solvent, such as DMF,and coupled with compound 3D using EDCl and HOBT at room temperatureovernight. After an aqueous/EtOAc work up, the product (compound 3E) wasisolated by chromatography.

In step 4, compound 3E was suspended in MeOH/water (1:1) under N₂atmosphere. NaOH and Zinc powder were added and the reaction mixture wasstirred at 70° C. to 80° C. for 8 to 24 hours. After cooling to roomtemperature, the solution was adjusted to pH=6˜7 with 1N HCl solution.The product (compound 3F) was extracted with EtOAc and purified byreverse phase HPLC.

Example 4

Step 3

A 25 mL flask was charged with compound 4C (331 mg, 1.68 mmol), compound4D (Strafford, E. S. and Curley, R. W. Jr, J. Med. Chem. 1983, 26,1463-1469) (200 mg, 1.4 mmol), EDCI (403 mg, 2.1 mmol), HOBT (227 mg,1.68 mmol), NMM (0.46 mL, 4.2 mmol), and DMF (7 mL). The solution wasstirred at room temperature overnight. Saturated aqueous NaHCO₃ (30 mL)and EtOAc (50 mL) were added. The organic phase was separated and washedwith water (20 mL) and brine (20 mL), then dried over Na₂SO₄. Thesolvent was evaporated and the crude product was isolated by silica gelchromatography (CH₂Cl₂/MeOH/NH₄OH 20:1:0.1 to 10:1:0.1) to give compound4E (201 mg, 45%).

Step 4

To a 10 mL flask was added compound 4E (50 mg, 0.155 mmol), NaOH (25 mg,0.62 mmol), Zinc powder (62 mg, 0.47 mmol), MeOH (0.5 mL), and water(0.5 mL). The solution was stirred at 75° C. for 16 hours. After coolingto room temperature, solid was removed by filtration. The filtrate wasadjusted to pH=5 by adding 2N HCl. The aqueous phase was extracted byEtOAc (10 mL). The organic solution was dried over Na₂SO₄ andconcentrated. The product was isolated by silica gel chromatography(CH₂Cl₂/MeOH/NH₄OH, 40:1:0.1 to 20:1:0.1 to 10:1:0.1) to give compound4F 6.5 mg (14%).

Example 5

Step 1

Compound 5A (1.33 g, 7.26 mmol), benzyl bromide (2.73 g, 16.0 mmol), andCs₂CO₃ (7.1 g, 22.0 mmol) were mixed in DMF (30 mL) and stirred at roomtemperature overnight. Saturated aqueous NaHCO₃ (100 mL) was added andthe aqueous phase was extracted with EtOAc (100 mL) twice. The combinedorganic phases were washed with brine (50 mL), dried over Na₂SO₄,filtered, and concentrated by rotary evaporator. The product wasisolated by silica gel chromatography (Hexane/EtOAc: 10:1 to 5:1) togive compound 5B (2.25 g, 89%).

Step 2

Compound 5B (2.25 g, 6.44 mmol) was dissolved in dioxane/water (3:1, 35mL) and LiOH (810 mg, 19.3 mmol) was added. The solution was stirred atroom temperature for 3 hours. Water (30 mL) was added followed byaddition of 2N HCl (30 mL). The aqueous phase was extracted with EtOAc(50 mL) three times. The organic phase was washed with brine, dried overNa₂SO₄, filtered, and concentrated by rotary evaporator. The crudeproduct was purified by silica gel chromatography (CH₂Cl₂/MeOH/HCO₂H:40:1:0.1 to 20:1:0.1) to give compound 5C (1.6 g, 91%).

The following compounds were prepared as described in Examples 3-5.

In each of the tables below, those compounds having a Ki value of lessthan 10 nM (<10 nM) are designated with letter “A”; those with a Kivalue of from 10 to less than 100 nM (10-<100 nM) are designated withletter “B”; those with a Ki value of from 100 to 1000 nM are designatedwith letter “C”; and those with a Ki value of more than 1000 nM (>1000nM) are designated with letter “D”.

TABLE 1 Exact Mass Compound # Structure Mass Obsvd Ki (nM) 1

290.27 291.1[M + H]⁺ B 2

366.13 367.1[M + H]⁺ C 3

304.12 305.0[M + H]⁺ C 4

352.12 353.1[M + H]⁺ A 5

382.13 383.1[M + H]⁺ B

Example 6

General Procedures for Example 6

In step 1,4-Bromo-2-nitro-benzoic acid (compound 6A) was dissolved in asuitable solvent, such as DMF, and reacted with methyl iodide in thepresence of cesium carbonate at room temperature for 2-16 hours. Waterand EtOAc were added and the organic phase was washed by water 1-5 timesto remove DMF. The organic phase was washed with brine, dried,concentrated, and dried to give the crude product (compound 6B) whichused without further purification.

In step 2, the methyl ester (compound 6B) was mixed with Pd(OAc)₂,Cs₂CO₃, and an appropriate ligand, such asracemic-2-(Di-t-butylphosphino)-1,1′-binaphthyl. The mixture was placedunder vacuum for 1 to 10 minutes to remove oxygen, and refilled with N₂.An alcohol and toluene were added and the solution was stirred at 50° C.to reflux temperature for 12 to 72 hours. After cooling to roomtemperature, the solid was removed by filtration and the solvent wasremoved. The product could be purified by chromatography. During thisreaction, the methyl ester may be partially converted to the ester ofthe alcohol used. This side product was also collected and hydrolyzed inthe next step.

In step 3, compound 6C was dissolved in Dioxane/water (3:1) and treatedwith lithium hydroxide at room temperature for 3-6 hours. The solutionwas made acidic by addition of 1N HCl solution and subjected toaqueous/EtOAc work up. The products (compound 6D) were either usedwithout further purification or purified by chromatography depending onthe boiling point of the alcohol side products.

In step 4, compound 6D was dissolved in a suitable solvent, such as DMF,and coupled with compound 6E under EDCl and HOBT conditions at roomtemperature overnight. After an aqueous/EtOAc work up, the product(compound 6F) could be isolated by chromatography.

In step 5, compound 6F was suspended in MeOH/water (1:1) under N₂atmosphere. NaOH and zinc powder were added and the reaction mixture wasstirred at 70° C. to 80° C. for 8 to 24 hours. After cooling to roomtemperature, the solution was adjusted to pH=6˜7 with 1N HCl solution.Compound 6G was extracted with EtOAc and isolated by reverse phase HPLC.

Example 7

Step 1

Compound 7A (10.0 g, 40.7 mmol) was dissolved in DMF (100 mL). Cs₂CO₃(27.0 g, 81.3 mmol) and methyl iodide (7.60 mL, 122.0 mmol) were added.The solution was stirred at room temperature overnight. EtOAc (250 mL)and water (100 mL) were added. The organic phase was separated andwashed with water (100 mL) three times and brine (50 mL), then driedover Na₂SO₄, filtered, and concentrated using a rotary evaporator. Theproduct was dried under vacuum to give compound 7B (10.3 g, 97%).

Step 2

Pd(OAc)₂ (43 mg, 0.19 mmol),racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (92 mg, 0.23 mmol), andCs₂CO₃ (1.88 g, 5.76 mmol) were placed in a 50 mL flask. The flask wasplaced under vacuum for 2 minutes and refilled with N₂. Compound 7B(1.00 g, 3.84 mmol) and MeOH (0.311 mL, 7.69 mmol) were dissolved intoluene (10 mL). The resulting solution was added to the above flask bypipette. The reaction mixture was stirred at 70° C. oil bath for 48hours. After cooling to room temperature, the solid was filtered and thesolvent was removed using a rotary evaporator. The product was isolatedby silica gel chromatography (Hexane/EtOAc 20:1 to 10:1) to givecompound 7C (380 mg, 47%).

Step 3

Compound 7C (380 mg, 1.80 mmol) was dissolved in dioxane/water (3:1, 8mL) and LiOH (378 mg, 9.0 mmol) was added. The solution was stirred atroom temperature for 3 hours. Water (5 mL) was added followed byaddition of 2N HCl to adjust the pH=2˜4. The aqueous phase was extractedwith EtOAc (10 mL) three times. The organic phase was washed with brine,dried over Na₂SO₄, filtered, and concentrated. The crude product wasdried under vacuum to give compound 7D which was used without furtherpurification.

The following compounds were prepared as described in Examples 6-7

TABLE 2 Exact Mass Compound # Structure Mass Obsvd Ki (nM) 6

289.11 291.1[M + H]⁺ B 7

366.13 367.1[M + H]⁺ C

Example 8

General Procedure for Example 8

In step 1, Compound 8A was dissolved in a suitable solvent, such as DMF,and reacted with methyl iodide in the presence of cesium carbonate atroom temperature for 2-16 hours. Water and EtOAc were added and theorganic phase was washed by water 1-5 times to remove DMF. The organicphase was washed with brine, dried, concentrated, and dried to give thecrude product (compound 8B) which was used without further purification.

In step 2, when alcohol was used, the reaction was operated in a similarmanner as step 2 in example 6. When an aromatic or heterocyclic stannanewas used, the reaction was operated in the following manner. Thearomatic or heterocyclic stannane was added into a dry flask, followedby addition of the 4-Bromo-2-methyl-benzoic acid methyl ester (compound8B), a base, such as Cs₂CO₃, K₃PO₄, and a palladium catalyst, such asPd(PPh₃)₂Cl₂. The flask was placed under vacuum for 1 to 10 minutes toremove oxygen and was refilled with N₂. An appropriate solvent, such asdry CH₃CN, was added and the solution was stirred at 60° C. to refluxtemperature overnight to 3 days. The solid was removed by filtration andthe solvent was removed. Compound 8C was isolated by chromatography.

In step 3, compound 8C was dissolved in a suitable inert solvent, suchas benzene, CCl₄ or α,α,α-Trifluorotoluene. NBS and benzoyl peroxidewere added and the solution was stirred at 50° C. to 90° C. for 1 to 24hours. The solid was filtered and the solvent was removed. The residuewas dissolved in ether and washed by water. The ether was removed toafford the compound 8D which was used without further purification.

In step 4, the benzyl bromide (compound 8D) was mixed with hydantoinmethyl amine 8E, K₂CO₃, and DMF. The solution was stirred at roomtemperature for 12 to 24 hours. Then the solid was removed byfiltration. The product could be purified by reverse phase HPLC.Compounds 8F and 8G could be obtained in a variable ratio.

Step 5 is used when the compound 8F was isolated in step 4. Compound 8Fwas dissolved in an appropriate solvent, such as MeOH, and stirred at50° C. to reflux temperature for 1 to 12 hours. The product could beobtained by removing the solvent by rotary evaporator or purifying viareverse phase chromatography.

Example 9

Step 3

Compound 9C (prepared according to the procedure described by Wyrick, S.D. et al. Journal of Medicinal Chemistry, 1987, 30(10), 1798-806) (3.33g, 18.5 mmol) was dissolved in dry benzene (40 mL). NBS (3.45 g, 19.4mmol) and benzoyl peroxide (134 mg, 0.55 mmol) were added. The solutionwas stirred in a 75° C. oil bath for about 2 hours. After cooling down,the solid was filtered and washed with Et₂O (150 mL). The organicsolution was then washed with water (50 mL) twice, dried over Na₂SO₄ orMgSO₄, filtered, and concentrated by rotary evaporator. The crudeproduct was dried under vacuum to give compound 9D which was usedwithout further purification. ¹H-NMR appeared to indicate thatapproximately 75% of this material was compound 9D.

Step 4

Compound 9D (4.62 mmol), Compound 9E (824 mg, 4.62 mmol), and K₂CO₃(1.28 g, 9.24 mmol) were mixed in DMF (30 mL). The solution was stirredat room temperature for 20 hours. DMF (15 mL) was added and the solidwas filtered and washed with DMF. All the DMF solution was combined andconcentrated to 25 mL. The resulting solution was applied to reversephase MPLC (CH₃CN/water, 5% to 90%, containing 0.1% HCO₂H) to givecompound 9F (198 mg, 15%).

Example 10

Step 4

Compound 10D (prepared in example 9) (902 mg, 2.07 mmol, factor=0.75),Compound 10E (prepared as described in Example 1, 500 mg, 2.07 mmol),and K₂CO₃ (629 mg, 4.56 mmol) were mixed in DMF (15 mL). The solutionwas stirred at room temperature for 20 hours. DMF (15 mL) was added andthe solid was filtered and washed with DMF. All the DMF solution wascombined and concentrated to 20 mL. It was applied to reverse phase MPLC(CH₃CN/water: 5% to 90%, containing 0.1% HCO₂H) to give compound 10F.

Step 5

Compound 10F (prepared in step 4) was dissolved in MeOH (5 mL), stirredat 65° C. for 5 hours, then concentrated to dryness. The compound wassuspended in water and dried with lyophilizer to give compound 10G (68.3mg, 9.4%).

Example 11

Step 2

Compound 11B (500 mg, 2.18 mmol), 2-tributylstannylthiazole (0.97 mL,2.84 mmol), Pd(PPh₃)₂Cl₂, and dry CH₃CN were stirred under nitrogen atreflux temperature overnight. After cooling to room temperature, thesolid was filtered. The product was isolated by silica gelchromatography (Hexane/EtOAc: 20:1 to 10:1 to 5:1) to give compound 11C(480 mg, 94%).

The following compounds were prepared as described in Examples 8-11.

TABLE 3 Exact Mass Compound # Structure Mass Obsvd Ki (nM) 8

289.11 290.1[M + H]⁺ B 9

351.12 352.1[M + H]⁺ A 10

337.01 338[M + H]⁺340.1 C 11

369.11 370.1[M + H]⁺ A 12

357.09 358.1[M + H]⁺ B 13

342.08 343.1[M + H]⁺ C 14

427.2 428.2[M + H]⁺ A 15

293.06 294.1[M + H]⁺ B 16

431.0 432.1[M + H]⁺ A 17

357.1 358.1[M + H]⁺ A 18

417.0 418.1[M + H]⁺ A 19

373.1 374.2[M + H]⁺ A

The following additional compounds were prepared as described inExamples 8 to 11.

TABLE 4 Exact Mass Compound # Structures Mass Obsvd Ki (nM) 294

350.08 351.1[M + H]⁺ B 295

335.10 336.1[M + H]⁺ B

Example 12

General Procedures for Example 12:

In step 1, racemic compound 12A was treated with one equivalent ofdi-tert-butyl dicarbonate and 4-N,N-dimethylaminopyridine in polarsolvent, such as DMF, for 30 minutes to 12 hours. The solvent wasremoved and the product (compound 12B) was isolated by silica gel(pretreated with 1% triethylamine in Hexane) chromatography.

In step 2, compound 12B was dissolved in proper solvents allowed by HPLCcolumn, and resolved by HPLC using a preparative Chiralpak AD orChiralcel OD column to give compound 12C and 12D.

In step 3, compound 12C and 12D were treated with excess HCl in methanolat 25° C. to 60° C. for one hour to 12 hours. The solvent wasconcentrated to give compound 12E and 12F.

Example 13

Step 1

Compound 13A (810 mg, 2.07 mmol), di-tert-butyl dicarbonate (429 mg,1.97 mmol), and 4-dimethylaminopyridine (20 mg) were dissolved in amixture of DMF (10 mL) and THF (20 mL). The solution was stirred at 25°C. overnight. Solvents were removed by rotary evaporator. The productwas isolated by C18 chromatography (CH₃CN/water: 5% to 90%) to giveproduct 13B (650 mg, 70%).

Step 2

Compound 13B (600 mg) was dissolved in a mixture of iso-propanol (6 mL)and CHCl₃ (4 mL). 2.5 mL was separated via HPLC with preparativechiralcel OD column (Mobile phase: iso-propanol/Hexane: 1:4). Fractionsfor each peak were collected and concentrated by rotary evaporator togive compound 13C (First peak, 197 mg) and compound 13D (second peak,178 mg).

Step 3

Compound 13C (197 mg) was dissolved in methanol (3 mL). HCl (4M inDioxane, 0.5 mL) was added. The solution was stirred in a 60° C. oilbath for three hours. Methanol was removed by rotary evaporator to givecompound 13E.

Compound 13F was prepared in the same way as compound 13D (178 mg).

The following compounds were prepared as described in Examples 12-13

TABLE 5 Exact Mass Compound # Structures Mass Obsvd Ki (nM) 20

Enantiomer A 351.1 352.2[M + H]⁺ A 21

Enantiomer B 351.1 352.2[M + H]⁺ C 22

Enantiomer A 357.1 358.1[M + H]⁺ C 23

Enantiomer B 357.1 358.1[M + H]⁺ A 24

Enantiomer A 373.06 374.2[M + H] C 25

Enantiomer B 373.06 374.2[M + H] AProton NMRSpectral Data for Selected Compounds in Table 5.

Compound 25. ¹H NMR (500 Hz, DMSO-d₆) δ 4.06 (d, J=14 Hz, 1H), 4.20 (d,J=14 Hz, 1H), 4.32 (d, J=18 Hz, 1H), 4.38 (d, J=18 Hz, 1H), 7.19-7.39(m, 2H), 7.55-7.80 (m, 5H), 8.93 (s, 1H), 10.96 (s, 1H).

Example 14

General Procedure for Example 14

In step 1, compound 14A (prepared as described in Example 1) was treatedwith a benzyl bromide (Compound 14B) and DIPEA base in DMF at 25° C. to60° C. for 12 to 24 hours. The reaction solution was purified via C18reverse phase chromatography to give compound 14C.

In step 2, compound 14C was treated with one equivalent di-tert-butyldicarbonate in polar solvent, such as DMF, for 30 minutes to 12 hours.The solvent was removed and the product (compound 14D) was isolated bysilica gel (pretreated with 1% triethylamine in Hexane) chromatography.

In step 3, compound 14D was subjected to either a Pd catalyzed reactionwith a heterocyclic boronic acid or a heterocyclic stannane, or a coppercatalyzed reaction with a heterocyclic amine. The reaction were heatedin appropriate solvents, such as DMF and acetonitrile, at 60° C. to 150°C., for 5 minutes to 12 hours. In some cases, a microwave reactor wasused. The product was purified by silica gel chromatography to givecompound 14E or compound 14F.

In step 4, compound 14E was dissolved in methanol and was stirred withHCl for 1 hour to 12 hours at 25° C. to 60° C. The solvent was removedto give compound 14F.

The following compounds were prepared as described in step 1 of Example14 above.

TABLE 6 Exact Mass Compound # Structure Mass Obsvd Ki (nM) 100

391.05 392.07[M + H]⁺ n/a 101

417.01 418.1[M + H]⁺ A 102

373.06 374.2[M + H]⁺ A 103

369.11 370.1[M + H]⁺ D 104

435.00 436.1[M + H]⁺ B 105

417.01 418.420[M + H]⁺ B 106

407.0 408[M + H]⁺ A 107

327.0 328[M + H]⁺ B 108

429.03 430.432[M + H]⁺ B 109

355.07 378.2[M + Na]⁺ B

EXAMPLE 15

Step 1

Compound 15A (prepared as described in Example 1, 1.0 g, 3.12 mmol),Compound 15B (prepared in Example 9, 1.06 g, 3.12 mmol, factor=0.76),and DIPEA base (1.14 mL, 6.55 mmol) were mixed in DMF (22 mL). Thesolution was stirred at 55° C. for 20 hours. The reaction solution waspurified via C18 reverse phase MPLC (130 g column, CH₃CN/water/0.1%HCO₂H, 5% to 90%, two separations) to give compound 15C (900 mg, 67%).

Step 2

Compound 15C (2.7 g, 6.28 mmol) was suspended in a mixture of DMF (20mL) and THF (40 mL). Di-tert-butyl dicarbonate (1.51 g, 6.91 mmol) and4-dimethyaminopyridine (38 mg, 0.31 mmol) were added. The solution wasstirred at 25° C. for 16 hours. The solvents were removed by rotaryevaporator. The residue was subjected to silica gel chromatography(Hexane/EtOAc: 2:1 to 1:1) to give compound 15D (2.36 g, 71%).

Step 3

Compound 15D (100 mg, 0.19 mmol), 3,4,5-trifluorophenyl boronic acid (40mg, 0.23 mmol), 1,1′-bis(triphenylphosphino)ferrocene palladium (II)chloride (15 mg, 0.02 mmol), potassium carbonate (1M in water, 1 mL) andacetonitrile (1 mL) were added to a microwave reactor tube. The tube wassealed and reacted in the microwave reactor at 150° C. for 10 minutes.After cooling down, the aqueous layer was removed and the organic layerwas concentrated. The crude product was purified by silica gelchromatography (CH₂Cl₂/MeOH/NH₃: 40:1:0.1) to give compound 15E.

Step 4

Compound 15E obtained from step 3 was suspended in MeOH. HCl (2M inethyl ether, 0.5 mL) was added. The reaction mixture was stirred at 50°C. for five hours. The solvent was removed. The product was purified viaC18 reverse phase chromatography (CH₃CN/water/0.1% HCO₂H, 5% to 90%) togive compound 15F (8 mg, 8.8% from compound 15D).

EXAMPLE 16

Step 3

Compound 16D (50 mg, 0.094 mmol, prepared in example 13),2-tributylstannylthiazole (53 mg, 0.14 mmol),dichlorobis(triphenylphosphine) palladium (II) (7 mg, 0.01 mmol), andacetonitrile (1 mL) were added to a microwave reactor tube. The tube wassealed and reacted in a microwave reactor at 150° C. for 10 minutes. Thesolvent was evaporated and the product was purified by silica gelchromatography (CH₂Cl₂/MeOH/NH₃: 40:1:0.1 to 20:1:0.1) to give compound16F (15 mg, 37%).

EXAMPLE 17

Step 3

Compound 17D (100 mg, 0.19 mmol, prepared in example 13), pyrazole (15.4mg, 0.23 mmol), cesium carbonate (124 mg, 0.38 mmol), copper iodide (7.2mg, 0.038 mmol), 1,10-phenanthroline (14 mg, 0.076 mmol), andN,N-dimethylacetamide (0.5 mL) were added to a dry reaction tube andfilled with nitrogen. The reaction tube was sealed and heated in a 120°C. oil bath for two days. After cooling down, the reaction solution waspurified by C18 chromatography (CH₃CN/water/0.1% HCO₂H, 5% to 90%) togive compound 17F (5 mg, 6.4%).

The following compounds were prepared as described in Examples 14-17

TABLE 7 Exact Mass Compound # Structure Mass Obsvd Ki (nM) 26

429.0 430.1[M + H]⁺ A 27

481.1 482.3[M + H]⁺ B 28

434.1 435.1[M + H]⁺ A 29

417.1 418.2[M + H]⁺ A 30

428.2 429.1[M + H]⁺ A

EXAMPLE 18

Step 1:

Compound 18A (1.0 g, 6.4 mmol) and compound 18B (1.324 g, 7.68 mmol)were dissolved in toluene (4 mL) and stirred at 80° C. for 24 hours.After cooling to room temperature, the solvent was removed by rotaryevaporator. Half of the crude product was dissolved in THF/1N HCl (1:1,14 mL) and stirred at room temperature for 2 hours. EtOAc (15 mL) andwater (5 mL) were added. The organic phase was separated and the aqueousphase was extracted with EtOAc (15 mL) twice. The combined organic phasewas dried over Na₂SO₄ and concentrated by rotary evaporator to givecompound 18C which was used without further purification.

Step 2

Compound 18C (prepared in step 1) was dissolved in DMF (15 mL) and wascooled to 0° C. in an ice-water bath. Compound 18D (571 mg, 3.2 mmol)was added in one portion. The solution was allowed to warm up to roomtemperature over 2 hours, and stirred at room temperature for 3 days. A2N HCl solution (20 mL) was added and the aqueous phase was extractedwith EtOAc (50 mL) three times. The organic phases were combined, driedover Na₂SO₄, and concentrated to dryness. The product was isolated byreverse phase LC (CH₃CN/water/0.1% HCO₂H: 5% to 90%) to give compound18E (65 mg, 7.4% from step 1) and Compound 18F (16 mg, 1.8% from step1).

The following compounds were prepared as described in Example 18

TABLE 8 Exact Mass Compound # Structure Mass Obsvd Ki (nM) 31

275.09 276.0[M + H]⁺ B 32

275.09 276.0[M + H]⁺ C

EXAMPLE 19

General Procedures for Example 19:

In step 1, compound 19A was treated with two equivalent of Boc₂O in asuitable solvent, such as dichloromethane, for 30 min. to 12 h. Thesolvent was removed and the compound 19B could be used without furtherpurification or purified by silica gel chromatography.

In step 2, compound 19B was treated with PCC and celite in a suitablesolvent such as dichloromethane, for 2 hr to 12 hr. Compound 19C waspurified by silica gel chromatography.

In step 3, compound 19C was reacted with potassium cyanide and ammoniumcarbonate in appropriated alcohol and water solution, at 50° C. to 90°C., for 5 hours to 48 hours. After cooling down, water was added andcompound 19D could be collected by filtration.

In step 4, compound 19D was stirred with 2 to 20 equivalents of hydrogenchloride in methanol for 5 to 48 hours. The solvent was removed and thecompound 19E could be used without further purification.

In step 5, the benzyl bromide (compound 19G) was mixed with hydantoinmethyl amine 19E, DIPEA, and DMF. The solution was stirred at roomtemperature for 12 to 24 hours. The product (19F) was either removed byfiltration or purified by silica gel chromatography.

EXAMPLE 20

General Procedures for Example 20:

In step 1, Compound 20A was treated with BOC—ON in a suitable solventsuch as dichloromethane, for 2 hr to 12 hr. Compound 20B was purified bysilica gel chromatography.

In step 2, Compound 20B was treated with CbzCl and a base such as DIPEA,in a suitable solvent, such as dichloromethane, for 2 hr to 12 hr.Compound 20C was purified by silica gel chromatography.

In step 3, compound 20C was treated with PCC and celite in a suitablesolvent such as dichloromethane, for 2 hr to 12 hr. Compound 20D waspurified by silica gel chromatography.

In step 4, compound 20D was reacted with potassium cyanide and ammoniumcarbonate in appropriated alcohol and water solution, at 50° C. to 90°C., for 1 hour to 48 hours. After cooling down, water was added andcompound 20E could be collected by filtration.

In step 5, Compound 20E was treated with Pd/C in a suitable solvent suchas methanol, in a par shaker under H₂ atmosphere. After filtering offthe catalyst and concentration of solvent, the product was used withoutfurther purification.

In step 6, the benzyl bromide (compound 20M) was mixed with hydantoinmethyl amine 20F, DIPEA, and DMF. The solution was stirred at roomtemperature to 80° C. for 12 to 24 hours. The product was either removedby filtration or purified by silica gel chromatography.

In step 7, compound 20G was stirred with 2 to 20 equivalents of hydrogenchloride in dioxane for 1 to 12 hours. The solvent was removed and thecompound 20H was used without further purification.

In step 8, Compound 20H was coupling with carboxylic acid to givecompound 20J which was purified by silica gel chromatography.

In step 9, Compound 20H was coupling with sulphonyl chloride compound togive compound 20L which was purified by silica gel chromatography.

In step 10, Compound 20H was reacted with carbonyl compound underreductive amination condition to give compound 20I. Alternatively,compound 20H was treated with a suitable electrophile and a base to givethe product 20I, which was purified by silica gel chromatography.

In step 11, compound 20I was reacted with carbonyl compound underreductive amination condition to give product 20K. Alternatively,compound 20I was treated with a suitable electrophile and a base to givethe product 20K, which was purified by silica gel chromatography.

EXAMPLE 21

Compound 21B: Compound 21A (7 g, 77.7 mmol), and di-tert-butyldicarbonate (35.6 g, 163 mmol) were stirred in methylene chloride (100mL) at 25° C. for 2 hr. Saturated aqueous NaCl (150 mL) was added. Theaqueous layer was extracted with CH₂Cl₂ (100 mL) twice. The organicphase was washed with brine (100 mL), dried over Na₂SO₄. The solvent wasremoved by rotary evaporator to give compound 21B (17 g, 76%) which wasused without further purification.

Compound 21C: compound 21B (17 g, 58.6 mmol) was dissolved in methylenechloride (100 mL). PCC (25.2 g, 117 mmol) and celite (15 g) were addedand the reaction mixture was stirred at 25° C. overnight. The solid wasfiltered off and the resulting solution was concentrated and purifiedvia sgc (40% EtOAc/Hexanes) to give 3.62 g (22%) of compound 21C.

Compound 21D: Compound 21C (3.62, 12.6 mmol), KCN (1.23 g, 18.9 mmol),and (NH₄)₂CO₃ (3.62 g, 37.7 mmol) were suspended in a mixture of EtOH(30 mL) and water (30 mL). The solution was stirred at 80° C. overnight.After cooling down, water (35 mL) was added. The solid was filtered andwashed with water three times. The solid was dried under vacuum to givecompound 21 D (3 g, 67%).

Compound 21E: Compound 21 D (3.0 g) was suspended in methanol (50 mL)and HCl (4M in dioxane, 20 mL) was added. The solution was stirred at25° C. for 3 hours. Ethyl ether (50 ml) was added. The solid wasfiltered, washed by ethyl ether twice, and dried under vacuum compound21E (1.34 g, 70%).

Compound 21F: Compound 21E (130 mg, 0.82 mmol), compound 21H (0.27 g, 1mmol) and DIPEA (0.55 mL, 2 mmol) were mixed in DMF (5 mL). The solutionwas stirred at room temperature overnight. Solvent was removed and thecrude material was and purified via sgc (5% NH₃. MeOH/CH₂Cl₂) to give129 mg (35%) of compound 21E.

EXAMPLE 22

Compound 22B: Compound 22A (7.3 g, 81 mmol) was treated with BOC—ON(21.9 g, 89 mmol) in dichloromethane for 3 hr. Solvent was removed andthe crude material was purified via sgc (10% NH₃. MeOH/CH₂Cl₂) to give6.5 (42%) of compound 22B.

Compound 22C: Compound 22B (1.5 g, 7.9 mmol) was dissolved indichloromethane (50 mL) at 0° C. CbzCl (1.24 ml, 8.7 mmol) and DIPEA(1.52 ml, 8.7 mmol) were added and the reaction was stirred at 0° C. for30 min. The reaction mixture was washed by HCl (1N, 50 mL) and brine (50mL). The organic layer was dried and concentrated to give crude compound22C (2.6 g, 99%) which was used without further purification.

Compound 22D: Compound 22C (2.78 g, 8.57 mmol) was dissolved inmethylene chloride (100 mL). PCC (4.62 g, 21.4 mmol) and celite (4.6 g)were added and the reaction mixture was stirred at 25° C. overnight.Another 0.5 eq. of PCC (923 mg, 4.3 mmol) was added and it was stirredfor 3 hr at room temperature. The solid was filtered off and theresulting solution was concentrated and purified via sgc (50%EtOAc/Hexanes) to give 1.86 g (73%) of compound 22D.

Compound 22E: Compound 22D (1.86, 5.8 mmol), KCN (0.56 g, 8.65 mmol),and (NH₄)₂CO₃ (1.66 g, 17.3 mmol) were suspended in a mixture of EtOH(20 mL) and water (20 mL). The solution was stirred at 80° C. overnight.After cooling down, EtOH was removed. The solid was filtered and washedwith water three times. The solid was dried under vacuum to givecompound 22E (1.45 g, 64%).

Compound 22F: Compound 22E (1.45 g, 3.68 mmol) was treated with Pd/C inmethanol in a par shaker under H₂ atmosphere of 50 psi for 60 hr. Afterfiltering off the catalyst and concentration of solvent, Compound 22E(0.95 g, 99%) was used without further purification.

Compound 22G: Compound 22F (150 mg, 0.58 mmol), compound 22M (170 mg,0.64 mmol) and DIPEA (0.22 mL, 1.28 mmol) were mixed in DMF (5 mL). Thesolution was stirred at 70° C. overnight. Solvent was removed and thecrude material was and purified via sgc (5% NH₃.MeOH/CH₂Cl₂) to give 166mg (71%) of compound 22G.

Compound 22H: Compound 22G (166 mg) was suspended in methanol (10 mL)and HCl (4M in dioxane, 4 mL) was added. The solution was stirred at 25°C. for 2 hours. Ethyl ether (50 ml) was added. Solvent was removed andgive compound 22H (0.14 g, 99%).

Compound 22I: Compound 22H (42 mg, 0.12 mmol) and compound 22J (26 mg,0.16 mmol) were dissolved in DMF (20 mL). EDCl (30 mg, 0.16 mmol), HOBT(21 mg, 0.16 mmol) and DIPEA (0.05 mL, 0.28 mmol) were added and thereaction mixture was stirred at room temperature for 2 hr. Solvent wasremoved and the crude material was and purified via sgc (10% NH₃.MeOH/CH₂Cl₂) to give 7 mg (13%) of compound 22I.

Compound 22L: Compound 22H (25 mg, 0.073 mmol) and cyclopentanone (7.5mg, 0.088 mmol) were stirred in methylene chloride (5 mL). Titaniumtetraisopropoxide (0.043 mL, 0.15 mmol) was added followed by additionof DIPEA (0.015 mL, 0.088 mmol). The reaction mixture was stirred atroom temperature for 2 h. Then, Na(OAc)₃BH (31 mg, 0.15 mmol) was addedand the mixture was stirred at rt overnight. Saturated K₂CO₃ aq. (20 mL)was added, and the mixture was stirred at rt briefly. The solid wasfiltered off through a celite pad. The filtrate was diluted withmethylene chloride (30 mL), and it was extracted with brine. The organiclayer was dried and concentrated to dryness. The crude material waspurified via PTLC (10% NH₃. MeOH/CH₂Cl₂) to give 7 mg (26%) of compound22L.

Compound 22K: Compound 22H (20 mg, 0.06 mmol) and isopropyl sulphonyl(27 mg, 0.18 mmol) were dissolved in methylene chloride (10 mL). DIPEA(0.04 mL, 0.26 mmol) were added and the reaction mixture was stirred atroom temperature for 48 hr. Solvent was removed and the crude materialwas and purified via sgc (10% NH₃. MeOH/CH₂Cl₂) to give 2 mg (8%) ofcompound 22K.

The following compounds were prepared as described in Examples 19-22.

TABLE 9 Exact Mass Compound # Structure Mass Obsvd Ki (nM) 33

450.15 451.1[M + H]⁺ B 34

458.05 459.3[M + H]⁺ B 35

447.15 448.2[M + H]⁺ A 36

372.18 373.2[M + H]⁺ B 37

332.15 333.1[M + H]⁺ C 38

358.16 359.2[M + H]⁺ B 39

380.12 381.2[M + H]⁺ C 40

417.12 418.1[M + H]⁺ D 41

386.09 387.2[M + H]⁺ C

EXAMPLE 1001

Step 1

To a solution of compound 1001A (1.65 g, 3.95 mmol) in anhydrous DMF (35mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl, 0.93 mL,4.73 mmol) and DIPEA (0.9 mL, 5.14 mmol). The solution was stirred at25° C. for overnight. DMF was removed under vacuum. The product 1001Bwas purified by SGC (Hexane/EtOAc, 2:1. yield: 1.6 g, 74%).

Step 2

Compound 1001B was resolved by Chiralcel OD column (Mobile phase:Hexane/2-propanol 3:1). The first peak was collected and concentrated togive compound 1001C.

Step 3

To a dry flask was added compound 1001C (1.5 g, 2.73 mmol) and 4-pyridylboronic acid (670 mg, 5.50 mmol). The flask was vacuumed and refilledwith nitrogen three times. Pd(dppf)Cl₂ (220 mg, 0.30 mmol) was added andfollowed by addition of CH₃CN (20 mL) and aq. K₂CO₃ (1 M, 15 mL). Thesolution was stirred at 80° C. (oil bath) for 16 hours. After coolingdown, CH₃CN (100 mL) was added and the solid was removed by filtration.The aqueous layer was separated and extracted with EtOAc (20 mL) once.The organic solution was combined and concentrated. The product waspurified by SGC (CH₂Cl₂/MeOH/NH₄OH: 20:1:0.1) to give compound 1001D.

Step 4

Compound 1001D was dissolved in a mixture of methanol and HCl (4M indioxane) (2:1, 30 mL) and was stirred overnight in a sealed pressureflask at 90° C. (oil bath). After the solution was cooled, the solutionwas transferred into a 250 mL round bottom flask. It was concentratedand dried under vacuum. The crude mixture was dissolved in methanol (50mL) and Et₃N (0.5 mL) was added and stirred overnight at 25° C. Thesolvent was then removed and the product was purified by C18 reversephase chromatography (CH₃CN/water 5% to 90%, with addition of 0.1%HCO₂H) to give compound 1001E (815 g, 71% from compound 1001C).

EXAMPLE 1002

To a flamed dried flask was added compound 1003A (100 mg, 0.182 mmol),[1,4-bis(diphenylphosphino)butane]palladium(II) dichloride [Pd(dppb)Cl₂,12 mg, 0.02 mmol], and copper (II) oxide (15 mg, 0.18 mmol). The flaskwas vacuumed and refilled with nitrogen. 2-Tri-n-butylstannylpyridine(0.076 mL, 0.237 mmol) and DMF (1 mL) were added. The solution wasstirred at 100° C. oil bath for 5 hours. After cooling, the DMF wasremoved by rotary evaporator. The product was purified by SGC(Hexane/EtOAc 2:1) to give 1003B (84 mg, 84%).

EXAMPLE 1003

To a dry pressure tube was added compound 1003A (50 mg, 0.091 mmol),bis(dibenzylideneacetone)palladium [Pd(dba)₂, 1.6 mg, 0.0018 mmol],9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos, 3.0 mg,0.0055 mmol), and Cs₂CO₃ (60 mg, 0.182 mmol). The pressure tube wasvacuumed and refilled with nitrogen. Pyrrolidinone (14 mg, 0.16 mmol)and dioxane(0.5 mL) were added. The tube was sealed and stirredovernight at 100° C. (oil bath). After cooling, dioxane (2 mL) was addedand the solid was removed by filtration. The solution was concentratedand purified by SGC (CH₂Cl₂/MeOH: 40:1) to give compound 1003B (27 mg).

EXAMPLE 1004

Step 1

Compound 1001C was prepared as described in Example 1001.

A mixture of compound 1001C (0.3 g, 0.55 mmol), bis(pinacolato)diboron(1004A; 170 mg, 0.65 mmol), potassium acetate (170 mg, 1.70 mmol), and[PdCl₂(dppf)]CH₂Cl₂ (50 mg, 0.05 mmol) in 1,4-dioxane (10 mL) wasvacuumed and refilled with argon three times. The reaction mixture wasstirred at 100° C. (oil bath) for 1.5 hours. After cooling down, themixture was diluted in EtOAc (50 mL) and filtered through a Celite pad.The filtrate was concentrated in vacuo and the residual material waspurified by silica gel column chromatography (2% MeOH in CH₂Cl₂) toafford compound 1004B (300 mg, 91% yield).

Step 2

A solution of compound 1004B (60 mg, 0.10 mmol),3-bromoimidazo[1,2-a]pyridine (30 mg, 0.15 mmol), and[PdCl₂(dppf)]CH₂Cl₂ (8.2 mg, 0.01 mmol) in CH₃CN (3 mL) was treated withpotassium carbonate (0.6 mL, 0.6 mmol, 1M in H₂O). The mixture wasvacuumed and refilled with argon three times. The reaction mixture wasstirred at 90° C. (oil bath) for 17 hours. After cooling, the mixturewas diluted in EtOAc (20 mL) and filtered through a Celite pad. Thefiltrate was concentrated in vacuo and the residual material waspurified by preparative TLC (10% MeOH in CH₂Cl₂) to afford compound1004C (42 mg, 71% yield).

The following compounds were prepared as described in Examples 1001,1002, 1003, or 1004.

TABLE 1000 Exact Mass Compound # Structure Mass Obsvd Ki (nM) 110

416.13 417.1[M + H]⁺ A 111

416.13 417.1[M + H]⁺ A 112

430.14 431.1[M + H]⁺ B 113

416.13 417.1[M + H]⁺ A 114

416.13 417.1[M + H]⁺ A 115

432.12 433.2[M + H]⁺ A 116

434.12 435.2[M + H]⁺ A 117

417.12 418.1[M + H]⁺ A 118

417.12 418.1[M + H]⁺ A 119

422.14 423.2[M + H]⁺ A 120

422.08 423.1[M + H]⁺ A 121

450.09 451.1[M + H]⁺ D 122

446.14 447.2[M + H]⁺ A 123

466.08 467.3[M + H]⁺ A 124

447.13 448.2[M + H]⁺ A 125

483.12 484.3[M + H]⁺ D 126

433.12 434.2[M + H]⁺ A 127

483.12 484.3[M + H]⁺ B 128

449.09 450.2[M + H]⁺ A 129

483.12 484.3[M + H]⁺ C 130

467.08 468.3[M + H]⁺ C 131

449.09 450.2[M + H]⁺ A 132

467.08 468.3[M + H]⁺ A 133

483.12 484.3[M + H]⁺ A 134

451.11 452.2[M + H]⁺ A 135

451.11 452.2[M + H]⁺ A 136

449.09 450.1[M + H]⁺ n/a 137

432.98 434.1[M + H]⁺ C 138

432.98 434.1[M + H]⁺ A 139

440.13 441.1[M + H]⁺ A 140

491.2 492.3[M + H]⁺ C 141

481.2 482.1[M + H]⁺ A 141

432.1 433.2[M + H]⁺ D 143

432.1 433.2[M + H]⁺ A 144

339.1 340[M + H]⁺ C 145

339.1 340[M + H]⁺ A 146

419.4 420.2[M + H]⁺ A 147

421.44 422.2[M + H]⁺ A 148

421.44 422.2[M + H]⁺ A 149

454.45 455.3[M + H]⁺ A 150

466.46 467.3[M + H]⁺ A 151

434.14 435.2[M + H]⁺ A 152

434.14 435.1[M + H]⁺ C 153

466.14 467.3[M + H]⁺ C 154

435.11 436.2[M + H]⁺ C 155

466.14 467.3[M + H]⁺ A 156

435.11 436.1[M + H]⁺ A 157

466.14 467.3[M + H]⁺ C 158

466.14 467.3[M + H]⁺ A 159

433.16 434.2[M + H]⁺ A 160

472.10 473.3[M + H]⁺ A 161

417.12 418.2[M + H]⁺ A 162

417.12 440.2[M + Na]⁺ C 163

466.14 467.3[M + H]⁺ B 164

405.12 406.2[M + H]⁺ A 165

466.14 467.3[M + H]⁺ A 166

455.44 456.3[M + H]⁺ n/a 167

464.15 465.3[M + H]⁺ A 168

516.18 517.1[M + H]⁺ C 169

478.16 479.3[M + H]⁺ A 170

516.18 517.3[M + H]⁺ n/a 171

466.46 467.3[M + H]⁺ B 172

405.38 406.2[M + H]⁺ A 173

466.46 467.3[M + H]⁺ A 174

432.12 433.1[M + H]⁺ A 175

466.08 467.1[M + H]⁺ A 176

430.14 431.2[M + H]⁺ DProton NMR Spectral Data for Selected Compounds in Table 1000.

Compound 111. ¹H-NMR (500 MHz, DMSO-d₆) δ 9.0 (s, 1H), 8.7 9(d, J=6.0Hz, 2H), 7.92 (d, J=8.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 7.76 (d, J=6.0Hz, 2H), 7.65 (m, 1H), 7.48 (m, 2H), 4.40 (d, J=17.3H, 1H), 4.31 (d,J=17.3 Hz, 1H), 4.27 (d, J=14.2 Hz, 1H), 4.14 (d, J=14.2 Hz, 1H).

Compound 120. ¹H-NMR (500 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.03 (d, J=8.8Hz, 2H), 7.96 (d, J=3.3 Hz, 1H), 7.84 (d, J=3.3 Hz, 1H), 7.77 (d, J=8.8Hz, 2H), 7.65 (s, 1H), 7.47 (m, 2H), 4.38 (d, J=17.6 Hz, 1H), 4.28 (d,J=17.6 Hz, 1H), 4.27 (d, J=14.3 Hz, 1H), 4.13 (d, J=14.3 Hz, 1H).

Compound 123. ¹H-NMR (500 MHz, DMSO-d₆) 68.99 (s, 1H), 7.84 (s, 1H),7.74 (d, J=8.4 Hz, 2H), 7.66 (dd, J=8.5, 4.6 Hz, 1H), 7.54 (d, J=8.4 Hz,2H), 7.49 (m, 2H), 6.65 (s, 1H), 4.40 (d, J=17.5 Hz, 1H), 4.31 (d,J=17.5 Hz, 1H), 4.29 (d, J=14.2 Hz, 1H), 4.10 9d, J=14.2 Hz, 1H).

Compound 139. ¹H NMR (500 MHz, CD₃OD) δ 3.17-3.21 (m, 4H), 3.83-3.88 (m,4H), 4.14-4.52 (m, 4H), 7.01 (d, J=8.8 Hz, 2H), 7.47 (d, J=8 Hz, 1H),7.46-7.48 (m, 3H), 7.75 (s, 1H).

Compound 143. ¹H NMR (400 MHz, CDCl₃) δ 4.21-4.50 (m, 4H), 7.498 (d,J=0.8 Hz, 1H), 7.52 (d, J=0.4 Hz, 1H), 7.73-7.76 (m, 3H), 7.76-7.87 (m,4H), 8.60 (d, J=6 Hz, 2H).

Compound 155. ¹H NMR (500 MHz, CD₃OD) δ 8.84 (dd, J=1.89, 4.1 Hz, 1H);8.43 (dd, J=1.58, 8.2 Hz, 1H); 7.99 (dd, J=1.58, 8.2 Hz; 1H); 7.85 (m,3H); 7.8 (dd, J=1.26 Hz, 6.94 Hz, 1H); 7.75 (m, 3H), 7.70 (dd, J=7.25Hz, 0.95 Hz, 1H); 7.59 (dd, J=4.73 Hz, 7.57 Hz, 1H); 7.58 (dd, J=4.4 Hz,8.2 Hz, 1H); 7.51 (dd, J=2.5 Hz, 7.8 Hz, 1H); 7.40 (m, 1H); 4.54 (d,J=17.0 Hz, 1H); 4.48 (d, J=17.0 Hz, 1H); 4.48 (d, J=14.5 Hz, 1H); 4.32(1H, d, J=14.5 Hz, 1H).

EXAMPLE 1005

General Procedure for Example 1005

Compound 1005A was treated with one equivalent of hexamethylenetetraamine in chloroform or other suitable solvent for about 5 hours.The product was collected by filtration and then treated with HCl inethanol for one day to three days. The solid was then collected byfiltration to give compound 1005B.

EXAMPLE 1006

1-Benzofuran-2-yl-2-bromo-ethanone (1006A, 3.0 g, 12.55 mmol),hexamethylene tetraamine (1.94 g, 13.80 mmol), and NaI (350 mg) werestirred in CHCl₃ (40 mL) for five hours. The solid was collected byfiltration and dried under vacuum. The solid was then suspended inethanol (30 mL) and HCl (conc, 36% in water, 10 mL) was added. Thesolution was stirred at 25° C. for 4 d. The solid was collected byfiltration and washed by ethanol, dried under vacuum to give compound1006B (3.05 g, contained NH₄Cl).

EXAMPLE 1007

Step 1

To a flame dried flask was added 2-bromo-1H-benzimidazole (1007A, 2.94g, 14.92 mmol), anhydrous THF (75 mL), and NaH (95%, 490 mg, 19.4 mmol).The solution was stirred at 25° C. for 45 minutes; SEMCl (3.17 mL, 17.9mmol) was added. The solution was stirred at 25° C. for 2.5 hours. Water(50 mL) and EtOAc (100 mL) were added. The aqueous layer was separatedand extracted with EtOAc (100 mL) once. The organic layers were combinedand concentrated under vacuum. The product was purified by SGC(Hexane/EtOAc: 3:1) to give compound 1007B (3.6 g, 74%).

Step 2

To a flame dried flask was added compound 1007B (1.427 g, 4.35 mmol) andanhydrous ethyl ether/THF (2:1, 15 mL). The solution was cooled to −78°C. n-Butyllithium (1.6 M, 0.46 mL, 0.73 mmol) was added and stirred at−78° C. for 30 minutes. In another flamed dried pear shaped flask wasadded N-(tert-butoxycarbonyl)glycine-N′-methoxy-N′-methylamide (949 mg,4.35 mmol) and anhydrous THF (2 mL). Isopropyl magnesium chloride (2 M,2.5 mL, 5.0 mmol) was added at 0° C. The solution was stirred at 0° C.for 5 minutes and was added into the compound 1003C solution via cannulaat −78° C. The solution was then gradually warmed up to −20° C. andstirred between −20° C. and 10° C. for 4 hours. Saturated NH₄Cl solutionwas added and the aqueous solution was extracted with EtOAc (50 mL)three times. The organic phases were combined and concentrated. Theproduct was purified by SGC (Hexane/EtOAc: 3:1) to give compound 1007C(1.0 g, 57%).

The following compounds were prepared as described in Example 1, 14,1005, 1006, and/or 1007.

TABLE 1001 Exact Mass Compound # Structure Mass Obsvd Ki (nM) 177

379.10 380.1[M + H]⁺ A 178

379.10 380.1[M + H]⁺ A 179

379.10 380.1[M + H]⁺ D 180

396.07 397.1[M + H]⁺ B 181

396.07 397.1[M + H]⁺ A 182

396.07 397.1[M + H]⁺ B 183

379.11 380.1[M + H]⁺ AProton NMR Spectral Data for Selected Compounds in Table 1003.

Compound 181. ¹H-NMR (500 MHz, DMSO-d₆) δ 11.3 (s, 1H), 9.34 (s, 1H),8.18 (d, J=8.5 Hz, 1H), 8.12 (d, J=7.6 Hz, 1H), 7.67 (m, 1H), 7.61 (m,1H), 7.50 (m, 3H), 4.65 (d, J=14.3 Hz, 1H), 4.44 (d, J=17.3 Hz, 1H),4.38 (d, J=17.3 Hz, 1H), 4.34 (d, J=14.3 Hz, 1H).

Example 1008

Compound 1008A (20 g, 81.61 mmol), 1008B (13.36 mL, 97.93 mmol),Pd(dppf)Cl₂ (1.0 g, 1.36 mmol), dioxane (350 mL), water (50 mL), andCs₂CO₃ (22.5 g, 163 mmol) were stirred at 110° C. (oil bath) undernitrogen for 16 hours. After cooling, the solid was removed byfiltration. The solution was concentrated and purified by SGC(Hexane/EtOAc, 10:1) to give 1008C (12.1 g, 80%).

The following compounds were prepared as described in Examples 14 and1008 and 1009.

TABLE 1002 Exact Mass Compound # Structure Mass Obsvd Ki (nM) 184

351.12 352.1[M + H]⁺ A 185

369.11 370.1[M + H]⁺ A 186

429.03 430.2[M + H]⁺432.2[M + Na]⁺ A

EXAMPLE 1009

Step 1

Compound 1009A (1.18 g, 3.36 mmol) and pyridine hydrochloride (2.33 g,20.17 mmol) were added into a 20 mL microwave reactor tube and reactedat 200° C. for 1 hour. After cooling down, the solid was dissolved inDMF and purified by C18 chromatography (CH₃CN/water 5% to 90%, with 0.1%HCO₂H) to give compound 1009B (0.87 g, 77%).

Step 2

Compound 1009B (0.75 g, 2.22 mmol) was dissolved in DMF (12 mL). SEMCl(0.48 mL, 2.44 mmol) and DIPEA (0.775 mL, 4.44 mmol) were added and thesolution was stirred at 25° C. for 4 hours. DMF was removed under vacuumand the product was purified by SGC (Hexane/EtOAc: 3:1 to 1:1) to givecompound 1009C (0.81 g, 78%).

Step 3

Compound 1009C was resolved on Chiralcel OD column by using Hexane and2-propanol as mobile phase. The first peak was collected andconcentrated to give compound 1009D.

Step 4

Compound 1009D (100 mg, 0.214 mmol), 1-bromo-2-butyne (34 mg, 0.257mmol), and Cs₂CO₃ (140 mg, 0.428 mmol) were stirred in DMF (2 mL) at 0°C. for 2 hours, then at 25° C. for overnight. Water (5 mL) was added andthe aqueous solution was extracted with EtOAc (10 mL) three times. Theorganic phases were combined and concentrated. The product was purifiedby SGC (Hexane/EtOAc: 3:1) to give compound 1009E (81 mg).

EXAMPLE 1010

Step 1

Compound 1010A (1.03 g, 1.88 mmol), (BOC)₂O (493 mg, 2.26 mmol), andCs₂CO₃ (741 mg, 2.26 mmol) were stirred overnight in CHCl₃ (20 mL).Water was added. The aqueous layer was extracted with EtOAc (3×50 mL).The combined organic layers were concentrated and purified by SGC(Hexane/EtOAc 5% to 90%) to give compound 1010B (1.01 g, 83%).

Step 2

To a dry flask was added compound 1010B (500 mg, 0.77 mmol) and4-pyridyl boronic acid (190 mg, 1.55 mmol). The flask was vacuumed andrefilled with nitrogen three times. Pd(dppf)Cl₂ (28 mg, 0.04 mmol) wasadded and followed by addition of CH₃CN (5 mL) and K₂CO₃ (1M, 4 mL). Thesolution was stirred at 80° C. (oil bath) for 16 hours. After coolingdown, CH₃CN (100 mL) was added and the solid was removed by filtration.The aqueous layer was separated and extracted once with EtOAc (20 mL).The organic solution was combined and concentrated. The product waspurified by SGC (CH₂Cl₂/MeOH/NH₄OH: 20:1:0.1) to give compound 1010C.

Step 3

Compound 1010C obtained in step 2 was dissolved in MeOH (10 mL) and HCl(4M in dioxane, 3 mL) was added and stirred overnight at 25° C. MeOH wasthen removed and the product was dried under vacuum to give compound1010D (315 mg, 75% from compound 1010B).

The following compounds were prepared as described in Examples 14 and1009 or 1010.

TABLE 1003 Exact Mass Compound # Structure Mass Obsvd Ki (nM) 187

337.11 338.1[M + H]⁺ B 188

337.11 338.1[M + H]⁺360.1[M + Na]⁺ A 189

337.11 338.2[M + H]⁺360.2[M + Na]⁺ A 190

437.16 438.2[M + H]⁺ A 191

492.18 493.3[M + H]⁺ A 192

492.18 493.3[M + H]⁺ C 193

430.16 431.1[M + H]⁺ A 194

430.16 431.1[M + H]⁺ A 195

554.2 555.1[M + H]⁺ B 196

492.16 493.1[M + H]⁺ A 197

492.16 493.1[M + H]⁺ A 198

389.14 390.1[M + H]⁺ A 199

355.10 356.1[M + H]⁺ C 200

554.20 555.1[M + H]⁺ B 201

415.02 416.2[M + H]⁺ B 202

466.16 467.1[M + H]⁺ A 203

407.13 408.2[M + H]⁺ A 204

482.16 483.3[M + H]⁺ A 205

355.1 356[M + H]⁺ A 206

400.99 402[M + H]⁺ C 207

480.99 482[M + H]⁺ D 208

572.19 573[M + H]⁺ B 209

510.17 511[M + H]⁺ A 210

459.16 460[M + H]⁺ D 211

407.13 408[M + H]⁺ A 212

355.1 356[M + H]⁺ C 213

355.1 356[M + H]⁺ A 214

415.02 416.418[M + H]⁺ A 215

467.05 468.470[M + H]⁺ A 216

518.2 519[M + H]⁺ C 217

480.1 481[M + H]⁺ A 218

452.1 453[M + H]⁺ B 219

409.14 410[M + H]⁺ A 220

411.16 412[M + H]⁺ A 221

531.19 532[M + H]⁺ B 222

485.1 486.488[M + H]⁺ A 223

446.14 447[M + H]⁺ A 224

465.21 466[M + H]⁺ C 225

558.09 559.561[M + H]⁺ A 226

487.04 488.490[M + H]⁺ A 227

591.11 592.1[M + H]⁺ B 228

519.1 520.1[M + H]⁺ C 229

528.1 529.4[M + H]⁺ B 230

407.13 408[M + H]⁺ A 231

459.16 460[M + H]⁺ C 232

421.14 422[M + H]⁺ A 233

471.08 472.474[M + H]⁺ C 234

415.02 416.418[M + H]⁺ A 235

429.03 430.432[M + H]⁺ A 236

466.16 467[M + H]⁺ A 237

431.44 432.2[M + H]⁺ A 238

417.41 418.2[M + H]⁺ n/a 239

423.12 424.2[M + H]⁺ A 240

423.12 424.2[M + H]⁺ A 241

482.16 483.3[M + H]⁺ A 242

355.10 356.2[M + H]⁺ A 243

409.14 410.2[M + H]⁺ A 244

423.12 424.1[M + H]⁺ n/a 245

435.16 436.2[M + H]⁺ n/a 246

469.14 470.3[M + H]⁺ n/aProton NMR Spectral Data for Selected Compounds in Table 1003.

Compound 198. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.22 (s, 1H), 7.64 (m,2H).7.43 (m, 4H), 7.22 (t, J=2.2 Hz, 1H), 7.16 (dd, J=9.6, 1.2 Hz, 1H). 4.82(d, J=2.0 Hz, 2H), 4.16 (m, 4H), 3.33 (s, 3H).

Compound 203. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.63 (dd, J=8.8, 5.6 Hz, 2H),7.43 (d, J=8.4 Hz, 1H), 7.13 (m, 4H), 4.80 (d, J=0.8 Hz, 1H), 4.39 (d,J=17.6 Hz, 1H), 4.17 (d, J=17.6 Hz, 1H), 4.13 (d, J=13.6 Hz, 1H), 3.71(d, J=13.6 Hz, 1H) 3.34 (s, 3H).

Compound 213. ¹H NMR (500 Hz, CD₃OD) δ 4.11 (d, J=15 Hz, 1H), 4.27 (d,J=15 Hz, 1H), 4.29 (d, J=17 Hz, 1H), 4.38 (d, J=17 Hz, 1H), 6.84-6.89(m,2H), 7.16-7.21 (m,2H), 7.56-7.60 (m, 1H), 7.71-7.76 (m,2H)

Compound 219. ¹H NMR (500 Hz, CD₃OD) δ 0.36-0.40 (m,2H), 0.61-0.68 (m,2H), 1.25-1.35 (m, 1H), 3.91 (d, J=7 Hz, 2H), 4.14 (d, J=15 Hz, 1H),4.30 (d, J=15 Hz, 1H), 4.34 (d, J=17 Hz, 1H), 4.43 (d, J=17 Hz, 1H),7.01-7.05 (m,2H), 7.17-7.23 (m,2H), 7.65-7.69 (m, 1H), 7.72-7.77 (m,2H)

Compound 232. ¹H NMR (500 Hz, CD₃OD) δ 1.13 (t, J=8 Hz, 3H), 2.21-2.27(m, 2H), 4.15 (d, J=14 Hz, 1H), 4.31 (d, J=14 Hz, 1H), 4.36 (d, J=17 Hz,1H), 4.45 (d, J=17 Hz, 1H), 4.79 (t, J=2 Hz, 2H), 7.04-7.14 (m, 2H),7.16-7.25 (m,2H), 7.64-7.79 (m, 3H).

Compound 233. ¹H NMR (500 Hz, CD₃OD) δ 7.678 (d, J=8.5 Hz, 1H); 7.455(d, J=4.1 Hz, 1H), 7.817 (d, J=4.1 Hz, 1H); 7.099 (s, 1H); 7.052 (dd,J=2.207, 6.305 Hz, 1H); 4.515 (d, J=17.3 Hz, 1H), 4.450 (d, J=17.3 Hz,1H); 4.065 (d, J=14.5 Hz, 1H); 3.89 (s, 3H); 3.87(d, J=14.5 Hz, 1H);3.85 (m, 1H); 2.46 (m. 2H); 2.09 (m, 1H) 1.89 (m, 1H); 1.76 (m, 1H);1.67(m, 1H); 1.54 (m, 1H); 1.32 (m, 1H).

Compound 239. ¹H NMR (500 Hz, DMSO-d₆) δ 4.11 (d, J=15 Hz, 1H), 4.27 (d,J=15 Hz, 1H), 4.29 (d, J=17 Hz, 1H), 4.38 (d, J=17 Hz, 1H), 6.84-6.89(m,2H), 7.16-7.21 (m,2H), 7.56-7.60 (m, 1H), 7.71-7.76 (m,2H)

Compound 243. ¹H-NMR (500 MHz, CD₃OD) δ 8.53 (s, 1H), 7.67 (dd, J=8.5, 5Hz, 2H), 7.46 (d, J=8 Hz, 1H), 7.27 (t, J=8.5 Hz, 2H), 7.15 (m, 2H),4.31 9d, J=17.0 Hz, 1H), 4.22 (d, J=17 Hz, 1H), 4.13 (d, J=14.2 Hz, 1H),4.06 (d, J=14.2 Hz, 1H), 3.88 9d, J=6.5 Hz, 2H), 3.35 9m, 2H), 1.22 (m,1H), 0.57 (d, J=8 Hz, 1H), 0.33 (d, J=5 Hz, 1H).

EXAMPLE 1011

To a solution of compound 1011A (100 mg) in DMF (5 mL) was addedm-chlorobenzoyl peroxide (MCPBA, 100 mg). The solution was stirredovernight at 25° C. The product was purified by C18 reverse phasechromatography (CH₃CN/water 5% to 90%, with 0.1% HCO₂H) to give compound1011B (73 mg).

The following compounds were prepared as described in Examples 1010 and1011.

TABLE 1004 Exact Mass Compound # Structure Mass Obsvd Ki (nM) 247

432.12 433.1[M + H]⁺ A

EXAMPLE 1012

In step 1, Compound 1012A was treated with nitromethane and KO^(t)Bu ina mixture of THF and t-BuOH for 2 to 12 h. Alternatively, compound 1012Awas treated with nitromethane and TBAF in a suitable solvent such as THFfor 2 to 12 h. Compound 1012B was purified by silica gel chromatography.

In step 2, Compound 1012B was treated with Pd/C in a suitable solventsuch as methanol, in a Parr shaker under H₂ atmosphere. After filteringoff the catalyst and concentration of solvent, the product was usedwithout further purification.

In step 3, the benzyl bromide (compound 1012D) was mixed with compound1012C, DIPEA, and DMF. The solution was stirred at 0° C. to roomtemperature for 12 to 24 hours. The product was either removed byfiltration or purified by silica gel chromatography.

In step 4, compound 1012E was treated with PCC and Celite in a suitablesolvent such as dichloromethane for 2 to 12 h. Compound 1012F waspurified by silica gel chromatography.

In step 5, compound 1012F was reacted with potassium cyanide andammonium carbonate in an appropriate alcohol and water solution, at 50°C. to 90° C., for 5 to 48 hours. After cooling, water was added andcompound 1012G was collected by filtration.

EXAMPLE 1013

Compound 1013B: To a solution of THF (15 mL) and t-BuOH (15 mL) wasadded compound 1013A (1.2 g, 5.6 mmol) and nitromethane (0.61 mL, 11.2mmol) followed by addition of KO^(t)Bu (0.63 g, 5.6 mmol). The reactionmixture was stirred at room temperature for 2 h. The reaction mixturewas adjusted to pH 6 using HOAc. The reaction mixture was diluted withEtOAc (30 mL), and was extracted with brine. The aqueous layer wasextracted with EtOAc (30 mL×2) The combined organic layers were washedwith brine, dried, and concentrated to dryness. The crude material waspurified via PTLC (25% EtOAc/Hexanes) to give 1.24 g (81%) of compound1013B.

Compound 1013C: Compound 1013B (1.24 g, 4.5 mmol) was treated with Pd/Cin methanol in a Parr shaker under H₂ atmosphere (50 psi) overnight.After filtering off the catalyst and concentration of solvent, compound1013C (1.1 g, 99%) was used without further purification.

Compound 1013E: Compound 1013C (1.02 g, 4.2 mmol) was dissolved indichloromethane (30 mL) at 0° C. Compound 1013D (1.13 g, 4.2 mmol) andDIPEA (0.73 mL, 4.2 mmol) were added and the reaction was stirred at 0°C. and slowly warmed up to rt overnight. The reaction mixture was washedwith HCl (1N, 50 mL) and brine (50 mL). The organic layer was dried andconcentrated to dryness. The crude material was purified via PTLC (50%EtOAc/Hexanes) to give 0.88 g (54%) of compound 1013E.

Compound 1013F: Compound 1013E (0.88 g, 2.25 mmol) was dissolved inmethylene chloride (30 mL). PCC (1.22 g, 5.63 mmol) and Celite (1.22 g)were added and the reaction mixture was stirred at 25° C. overnight. Thesolid was filtered off and the resulting solution was concentrated andpurified via sgc (90% EtOAc/Hexanes) to give 0.62 g (71%) of compound1013F.

Compound 1013G: Compound 1013F (1.01 g, 2.6 mmol), KCN (0.25 g, 3.9mmol), and (NH₄)₂CO₃ (0.75 g, 7.8 mmol) were suspended in a mixture ofNH₃ in Methanol (7 N, 10 mL) and water (10 mL). The solution was stirredat 90° C. overnight. After cooling, water (20 mL) was added. The solidwas filtered and washed with water three times. The solid was driedunder vacuum to give compound 1013G (0.86 g, 72%).

EXAMPLE 1014

Step 1.

Compound 1014A was stirred with 2 to 20 equivalents of hydrogen chloridein methanol for 5 to 48 hours. The solvent was removed and the compound1014B could be used without further purification.

Step 2.

Compound 1014B was treated with carboxylic anhydride and DIPEA to givecompound 1014C which was purified by silica gel chromatography.

Step 3.

Compound 1014B was coupled with sulphonyl chloride compound to givecompound 1014D, which was purified by silica gel chromatography.

Step 4.

Compound 1014B was reacted with carbonyl compound under reductiveamination conditions to give compound 1014E. Alternatively, compound1014B was treated with a suitable electrophile and a base to givecompound 1014E, which was purified by silica gel chromatography.

Step 5.

Compound 1014B was reacted with isocyanate compound and DIPEA to givecompound 1014F, which was purified by silica gel chromatography.

EXAMPLE 1015

Compound 1015B: Compound 1015A(0.86 g) was suspended in methanol (10 mL)and HCl (4M in dioxane, 10 mL) was added. The solution was stirred at25° C. for 3 hours. Solvent was removed and the material was dried undervacuum to give compound 1015B (0.74 g, 99%).

Compound 1015C: Compound 1015B (40 mg, 0.11 mmol) and benzoic acidanhydride (25 mg, 0.11 mmol) were dissolved in DMF (1 mL). DIPEA (0.06mL, 0.33 mmol) was added and the reaction mixture was stirred at roomtemperature overnight. Solvent was removed and the crude material waspurified via sgc (5% NH₃.MeOH/CH₂Cl₂) to give 3.7 mg (7%) of compound1015C.

Compound 1015D: Compound 1015B (40 mg, 0.11 mmol) and compound 1015H (30mg, 0.11 mmol) were dissolved in DMF (1 mL). DIPEA (0.25 mL, 1.4 mmol)was added and the reaction mixture was stirred at room temperatureovernight. Solvent was removed and the crude material was purified viasgc (5% NH₃. MeOH/CH₂Cl₂) to give 2.2 mg (3%) of compound 1015D.

Compound 1015E: Compound 1015B (40 mg, 0.11 mmol) and compound 1015I(0.024 mL, 0.22 mmol) were dissolved in DMF (1 mL). K₂CO₃ (46 mg, 0.33mmol) was added and the reaction mixture was stirred at 90° C.overnight. Solvent was removed and the crude material was purified viasgc (5% NH₃. MeOH/CH₂Cl₂) to give 2.6 mg (5%) of compound 1015E.

Compound 1015F: Compound 1015B (46 mg, 0.13 mmol) and cyclobutanone (0.2mL) were stirred in methylene chloride (1 mL). Titaniumtetraisopropoxide (0.045 mL, 0.15 mmol) was added followed by additionof DIPEA (0.027 mL, 0.16 mmol). The reaction mixture was stirred at roomtemperature for 2 h. Then, NaCNBH₃ (41 mg, 0.65 mmol) was added and themixture was stirred at rt overnight. The solvent was removed. The crudematerial was purified via PTLC (10% NH₃.MeOH/CH₂Cl₂) to give 3.1 mg (6%)of compound 1015F.

Compound 1015G: Compound 1015B (80 mg, 0.24 mmol) and ethyl isocyanate(0.018 mL, 0.24 mmol) were dissolved in DMF (1 mL). DIPEA (0.17 mL, 0.97mmol) was added and the reaction mixture was stirred at room temperatureovernight. Solvent was removed and the crude material was purified viasgc (9% NH₃. MeOH/CH₂Cl₂) to give 11 mg (11%) of compound 1015G.

The following compounds were prepared as described in Examples 1012 to1015.

TABLE 1005 Exact Mass Compound # Structure Mass Obsvd Ki (nM) 248

379.09 380.1[M + H]⁺ C 249

379.09 380.1[M + H]⁺ C 250

421.09 422.1[M + H]⁺ B 251

421.09 422.1[M + H]⁺ A 252

436.14 437.1[M + H]⁺ B 253

429.2 430.1[M + H]⁺ B 254

534.14 535.1[M + H]⁺ B 255

528.17 529.3[M + H]⁺ B 256

548.17 549.3[M + H]⁺ A 257

499.15 500.3[M + H]⁺ B 258

571.12 572.1[M + H]⁺ A 259

538.07 539.1[M + H]⁺ A 260

390.11 391.1[M + H]⁺ A 261

402.13 403.2[M + H]⁺ A 262

390.11 391.1[M + H]⁺ A 263

402.13 403.1[M + H]⁺ A 264

433.11 434.1[M + H]⁺ A 265

582.02 585.1[M + H]⁺ A 266

504.11 505.1[M + H]⁺ A 267

462.19 463.1[M + H]⁺ B 268

400.17 401.1[M + H]⁺ A 269

459.19 460.1[M + H]⁺ B 270

436.19 437.2[M + H]⁺ B 271

532.12 533.3[M + H]⁺ B 272

412.21 413.2[M + H]⁺ C 273

441.24 442.1[M + H]⁺ C 274

541.29 542.3[M + H]⁺ C 275

426.23 427.2[M + H]⁺ C 276

358.16 359.1[M + H]⁺ C 277

458.22 459.1[M + H]⁺ BProton NMR Spectral Data for Selected Compounds in Table 1005.

Compound 262. ¹H NMR (500 Hz, CD₃OD) δ 8.921 (m, 1H); 8.433 (d, J=8.6Hz, 1H); 8.357 (s, 1H); 8.072 (m, 4H); 7.622 (m, 1H); 7.545 (m, 1H);7.476 (m, 1H); 7.369 (m, 1H); 4.522 (d, J=17 Hz, 1H); 4.510 (d, J=14.5Hz, 1H); 4.425 (d, J=17 Hz, 1H), 4.350 (d, J=14.5 Hz, 1H).

EXAMPLE 1016

Compound 1016B: Compound 1016A (500 mg, 1.77 mmol) was suspended inCH₃CN (5 mL) followed by addition of NaN(CHO)₂ (202 mg, 2.12 mmol). Thereaction mixture was stirred at rt for 30 min before warmed up to 70° C.and stirred for 2 h. Solid was collected by suction filtration andwashed with acetonitrile to give 1016B (380 mg, 78%) as brown solid.

Compound 1016C: Compound 1016B (380 mg, 1.38 mmol) was stirred with HCl(36% aq., 1 mL) and EtOH (10 mL) at rt for 2 days. It was then heated to60° C. for 2 hr. Solvent was removed and it was dried under vacuum togive 1016C (345 mg, 98%). The material was used without furtherpurification.

The following compounds were prepared as described in Example 1016,Example 2 and Example 8.

TABLE 1006 Com- Exact Mass pound # Structure Mass Obsvd Ki (nM) 278

422.08 423.1[M + H]⁺ A 279

422.08 423.1[M + H]⁺ C 280

420.9 421.1[M + H]⁺ A 281

434.1 435.2[M + H]⁺ AProton NMR Spectral Data for Selected Compounds in Table 1006. Compound278. ¹H NMR (500 Hz, CD₃OD) δ 8.503 (d, J=4.73 Hz, 1H); 7.84 (m, 2H);7.67 (d, J=3.8 Hz, 1H); 7.56 (dd, J=4.4 Hz, 8.5 Hz, 1H); 7.50 (dd, J=2.5Hz, 7.8 Hz, 1H); 7.38 (m, 1H); 7.33 (d, J=4.1 Hz, 2H); 7.3 (m, 1H); 4.52(d, J=17 Hz, 1H); 4.45 (d, J=17 Hz, 1H); 4.43 (d, J=14.2 Hz, 1H); 4.28(d, J=14.2 Hz, 1H).

EXAMPLE 1017

Compound 1017C: Compound 1017A (1.5 g, 8.26 mmol) was dissolved indichloromethane (20 mL) and methanol (10 mL) at 0° C. Compound 1017B(2.64 g, 10 mmol) and DIPEA (2.9 mL, 16.5 mmol) were added and thereaction was stirred at 0° C. and slowly warmed up to rt overnight. Thereaction mixture was then heated to 50° C. and stirred for 2 h. Thereaction mixture was washed with brine (50 mL). The organic layer wasdried and concentrated to dryness. The crude material was purified viaPTLC (50% EtOAc/hexanes) to give 0.7 g (29%) of compound 1017C.

Compound 1017D: Compound 1017C (200 mg, 0.68 mmol) was stirred in CH₂Cl₂(15 mL) at 0° C. followed by addition of compound 1017I (0.5 mL, 2.04mmol) and TMS-OTf (13 μL, 0.07 mmol). The reaction mixture was stirredat 0° C. to 5° C. for 6 hr before warmed up to rt and stirred overnight.The solvent was removed and the crude material was purified via PTLC(EtOAc) to give 0.21 g (91%) of compound 1017D.

Compound 1017E: Compound 1017D (210 mg, 0.62 mmol) was heated in asealed tube with NH₂NH₂ (0.2 mL, 6.2 mmol) and EtOH (2 mL) at 60° C.overnight. Solvent was removed and gave crude material 1017E (210 mg,99%) which was used without further purification.

Compound 1017F: Compound 1017E (210 mg, 0.62 mmol) and ethyl isocyanate(59 μL, 0.74 mmol) were dissolved in CH₂Cl₂ (10 mL). The reactionmixture was stirred at room temperature overnight. To this mixture wasadded Et₃N (0.43 mL, 3.1 mmol), DMAP (15 mg, cat.) and p-TsCl (141 mg,0.74 mmol). The reaction was stirred at rt overnight. Solvent wasremoved and the crude material was purified via sgc (10% NH₃.MeOH/CH₂Cl₂) to give 60 mg (25%) of compound 1017F.

Compound 1017G: Compound 1017F (60 mg, 0.15 mmol) was heated in a sealedtube with HCl (3 mL, 4N in dioxane) at 65° C. for 48 hr. Solvent wasremoved and the crude material was purified via sgc (5% NH₃.MeOH/CH₂Cl₂) to give 35 mg (66%) of compound 1017G.

Compound 1017H: Compound 1017G (34 mg, 0.1 mmol), KCN (10 mg, 0.15mmol), and (NH₄)₂CO₃ (30 mg, 0.3 mmol) were suspended in a mixture ofNH₃. H₂O (1 mL) and ethanol (1 mL). The solution was stirred at 90° C.overnight. Solvent was removed and the crude material was purified viasgc (10% NH₃. MeOH/CH₂Cl₂) to give 6 mg (15%) of compound 1017H.

The following compounds were prepared as described in Example 1017

TABLE 1007 Exact Mass Compound # Structure Mass Obsvd Ki (nM) 282

418.12 419.1[M + H]⁺ B

EXAMPLE 1018

Compound 1018A: Compound 1018A was synthesized following procedures inExample 1012.

Compound 1018B: Compound 1018A (180 mg, 047 mmol) was stirred in MeOH (1mL) at rt. HCl (3 mL, 4N in dioxane) was added and the reaction mixturewas heated to 70° C. overnight. Solvent was evaporated. The crudematerial was taken up in water and the solid was collected by suctionfiltration to give 1018B (115 mg, 71%).

EXAMPLE 1019

Compound 1019A: Compound 1019A was synthesized following proceduresdescribed in Example 1012.

Compound 1019B: Compound 1019A (74 mg, 0.18 mmol) was dissolved in EtOH(2 mL) and HCl (0.4 mL, aq. 36%) was added and the reaction mixture washeated to 70° C. overnight. Solvent was removed and gave 1019B as alight yellow solid (74 mg, 99%).

Compound 1019C: Compound 1019B (20 mg, 0.05 mmol) was stirred in DMF (1mL) and HCl (cat., 4 N in dioxane) at 120° C. overnight. Solvent wasremoved and the crude material was purified via PTLC (9% NH₃.MeOH/CH₂Cl₂) to give 8 mg (37%) of Compound 1019C.

The following compounds were prepared as described in Example 1012, 1018and 1019.

TABLE 1008 Com- Exact Mass pound # Structure Mass Obsvd Ki (nM) 283

339.06 340.2[M + H]⁺ B 284

339.06 340.2[M + H]⁺ D 285

408.14 409.2[M + H]⁺ A 286

366.13 367.1[M + H]⁺ A 287

394.13 395.2[M + H]⁺ B

EXAMPLE 1020

Compound 1020A: Compound 1020A was synthesized following the proceduresdescribed in Example 22.

Compound 1020B: Compound 1020A (855 mg, 1.86 mmol) was stirred in MeOH(10 mL) and HCl (10 mL, 4N in dioxane) at rt for 2 hr. Solvent wasremoved and the material was dried to give 1020B (735 mg, 99%).

The following compounds were prepared as described in Example 22 andExample 1020.

TABLE 1009 Exact Mass Compound # Structure Mass Obsvd Ki (nM) 288

487.24 488.3[M + H]⁺ B 289

387.19 388.1[M + H]⁺ C 290

501.26 502.3[M + H]⁺ B 291

401.21 402.2[M + H]⁺ C 292

501.26 502.3[M + H]⁺ B 293

401.21 402.1[M + H]⁺ B

EXAMPLE 1021

Step 1

DMF (100 mL), cesium carbonate (41.13 g, 126 mmol), and2-chloro-5-methylphenol (1021A) (15.0 g, 105 mmol) were added to aflask. Methyl iodide (17.92 g, 126 mmol) was added dropwise via additionfunnel. The reaction mixture was stirred overnight at room temperature.The reaction mixture was diluted with EtOAc, washed with water andbrine, and dried with Na₂SO₄. The resulting material was filtered, andconcentrated to dryness. The crude product was purified via flash sgcusing 1:4 EtOAc:hexanes as the mobile phase to give 15.93 g of 1021B.

Step 2

A flask containing AlCl₃ (2.55 g, 19.1 mmol), and LiCl (0.41 g, 9.6mmol) was placed in a −30° C. cold bath. A solution of 1021B (1.0 g,6.38 mmol) and acetyl chloride (0.75 g, 9.5 mmol) in 20 mL of CH₂Cl₂ wasadded dropwise. The reaction mixture was stirred for 1 h at −30° C.,then allowed to warm to rt and stirred overnight at rt. The reactionmixture was poured into a mixture of ice and EtOAc. The organic layerwas washed with water, saturated aq NaHCO₃, and water, then dried withNa₂SO₄, and concentrated to dryness to give 1.18 g of Compound 1021C.

Step 3

Sodium hydroxide (58 g, 1.45 mol) was dissolved in water (260 mL) andthe flask was cooled in an ice-water bath. Bromine (19 mL) was addeddropwise to the flask with stirring. The reaction mixture was stirredfor 0.5 h after the addition was complete. The resulting solution wasadded dropwise to an ice-water cooled flask containing Compound 1021C(18.5 g, 93.1 mmol). After the addition was complete, the reactionmixture was allowed to warm to rt and left stirring overnight. Thereaction mixture was heated at 40° C. for 2 h. NaHSO₃ (55 g) was added.The reaction mixture was stirred for 1 h. The resulting material wasdiluted with 10% aq NaOH and extracted with EtOAc to remove startingmaterial. The aqueous layer was adjusted to pH 1 and extracted withadditional EtOAc. The organic layer was dried with Na₂SO₄, filtered, andconcentrated to dryness to give 12.31 g of 1021D.

Step 4

DMF (10 mL), Compound 1021D (0.50 g, 2.49 mmol), and K₂CO₃ (0.41 g, 2.96mmol) were added to a flask. Methyl iodide (0.42 g, 2.96 mmol) was addeddropwise. The reaction mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated to dryness to give0.52 g of 1021E.

The following compounds were prepared as described in step 1 in Example14 and Example 1021.

TABLE 1010 Exact Mass Compound # Structure Mass Obsvd Ki (nM) 296

403.07 404.2[M + H]⁺ A 297

389.06 390.2[M + H]⁺ A 298

403.07 404.1[M + H]⁺ n/aProton NMR Spectral Data for Selected Compounds in Table 1010.

Compound 296. ¹H NMR (500 Hz, DMSO-d₆) δ 3.93 (s, 3H), 4.00 (d, J=14 Hz,1H), 4.19 (d, J=14 Hz, 1H), 4.23 (d, J=18 Hz, 1H), 4.34 (d, J=18 Hz,1H), 7.24-7.34 (m, 2H), 7.42 (s, 1H), 7.62-7.73 (m, 3H), 8.92 (s, 1H),10.95 (s, 1H).

Specific TACE inhibitory activity (Ki values) of some representativecompounds of the present invention are set forth below.

TABLE 1011 Compound # Structure Ki (nM) 111

0.48 120

4 213

0.8 181

3.17 262

4.91 198

1.29 143

1.87 219

2.4 155

1.05 296

1.01 123

1.2 232

1.0 233

2.35 278

2.2 139

2.8 25

0.43 203

0.23 239

0.11 243

3.00

The following additional compounds were also prepared by proceduresdescribed above as well as in the description discussed later.

TABLE 3000 Compound Exact Mass Ki ID Structures Mass Obsvd Rating 3000

419.14 420.1[M + H]⁺ C 3001

518.20 519.1[M + H]⁺ B 3002

419.14 420.1[M + H]⁺ A 3003

728.71 729.2[M + H]⁺ D 3004

447.13 448.2[M + H]⁺ C 3005

469.16 470.3[M + H]⁺ A 3006

523.13 524.3[M + H]⁺ A 3007

532.20 533.3[M + H]⁺ A 3008

481.20 482.3[M + H]⁺ B 3009

478.16 479.3[M + H]⁺ A 3010

492.20 493.3[M + H]⁺ A 3011

472.10 473.3[M + H]⁺ A 3012

480.20 481.3[M + H]⁺ D 3013

480.20 481.3[M + H]⁺ A 3014

542.20 543.3[M + H]⁺ B 3015

445.20 446.2[M + H]⁺ A 3016

446.20 447.2[M + H]⁺ A 3017

535.15 536.3[M + H]⁺ B 3018

499.10 500.3[M + H]⁺ B 3019

507.20 508.3[M + H]⁺ A 3020

577.19 578.3[M + H]⁺ B 3021

512.13 513.3[M + H]⁺ D 3022

512.13 513.3[M + H]⁺ B 3023

354.34 355.2[M + H]⁺ D 3024

498.12 499.3[M + H]⁺ C 3025

498.12 499.3[M + H]⁺ B 3026

482.14 483.3[M + H]⁺ B 3027

471.15 472.3[M + H]⁺ D 3028

472.10 473.3[M + H]⁺ C 3029

471.15 472.3[M + H]⁺ A 3030

472.10 473.3[M + H]⁺ A 3031

447.17 448.2[M + H]⁺ A 3032

483.17 484.3[M + H]⁺ A 3033

459.19 460.3[M + H]⁺ A 3034

510.14 511.3[M + H]⁺ A 3035

497.21 498.3[M + H]⁺ A 3003

523.20 524.3[M + H]⁺ A 3037

549.24 550.3[M + H]⁺ A 3038

523.20 524.3[M + H]⁺ A 3039

511.20 512.3[M + H]⁺ A 3040

511.20 512.3[M + H]⁺ A 3041

513.20 514.3[M + H]⁺ A 3042

584.12 585.3[M + H]⁺ A 3043

525.14 526.3[M + H]⁺ C 3044

525.14 526.3[M + H]⁺ A 3045

561.21 562.3[M + H]⁺ A 3046

549.21 550.3[M + H]⁺ A 3047

493.18 494.3[M + H]⁺ A 3048

519.15 520.3[M + H]⁺ A 4001

433.1 434.2[M + H]⁺ A 4002

375.1 376.1[M + H]⁺ A 4003

407.1 408.2[M + H]⁺ A 4004

423.2 424.2[M + H]⁺ A 4005

446.1 447.2[M + H]⁺ A 4006

373.1 374.2[M + H]⁺ C 4007

512.2 513.3[M + H]⁺ A 4008

439.2 440.2[M + H]⁺ B 4009

415.1 416.2[M + H]⁺ B 4010

483.2 484.3[M + H]⁺ A 4011

483.2 484.3[M + H]⁺ C 4012

467.2 468.3[M + H]⁺ A 4013

429.2 430.2[M + H]⁺ A 4014

484.2 485.3[M + H]⁺ A 4015

482.2 483.3[M + H]⁺ A 4016

419.1 420.0[M + H]⁺ A 4017

482.2 483.3[M + H]⁺ A 4018

480.2 481.3[M + H]⁺ A 4019

433.1 434.2[M + H]⁺ C 4020

445.1 446.2[M + H]⁺ A 4021

484.1 485.3[M + H]⁺ A 4022

442.2 443.2[M + H]⁺ A 4023

447.2 448.2[M + H]⁺ A 4024

453.1 454.2[M + H]⁺ A 4025

458.2 459.3[M + H]⁺ A 4026

496.2 497.3[M + H]⁺ A 4027

443.2 444.2[M + H]⁺ A 4028

497.1 498.3[M + H]⁺ B 4029

461.1 462.3[M + H]⁺ A 4030

445.1 446.2[M + H]⁺ A 4031

429.1 430.2[M + H]⁺ A 4032

499.1 500.3[M + H]⁺ A 4033

493.2 494.3[M + H]⁺ A 4034

493.2 494.3[M + H]⁺ B 4035

442.2 443.2[M + H]⁺ A 4036

442.2 443.2[M + H]⁺ n/a 4037

443.2 444.2[M + H]⁺ n/a 4038

443.2 444.2[M + H]⁺ n/a 4039

457.2 458.3[M + H]⁺ n/a 4040

457.2 458.3[M + H]⁺ n/a 4041

444.1 445.2[M + H]⁺ n/a 4042

444.1 445.2[M + H]⁺ n/a 5000

321.1 322.2[M + H]⁺ 5001

475.1 476.3[M + H]⁺ 5003

407.1 408.2[M + H]⁺ B 5004

327.1 328.2[M + H]⁺ C 5005

457.2 458.3[M + H]⁺ A 5006

471.2 472.1[M + H]⁺ A 50071338095

509.2 510.3[M + H]⁺ A 5008

361.08 362.2[M + H]⁺ B 5009

389.1 390.2[M + H]⁺ A 5010

405.1 406.2[M + H]⁺ A 5011

289.1 290.2[M + H]⁺ B 5012

323.1 324.2[M + H]⁺ B 5013

309.1 310.2[M + H]⁺ C 5014

377.1 378.2[M + H]⁺ C 5015

289.1 290.2[M + H]⁺ B 5016

367.1 368.2[M + H]⁺ B 5017

409.2 410.2[M + H]⁺ A 5018

365.14 366.2[M + H]⁺ A 5019

367.12 368.2[M + H]⁺ A 5020

435.2 436.2[M + H]⁺ A 5021

409.2 410.2[M + H]⁺ A 5022

435.2 436.2[M + H]⁺ A 5023

419.2 420.2[M + H]⁺ A 5024

435.1 436.2[M + H]⁺ A 5025

458.2 459.3[M + H]⁺ A 6000

434.39 435.4[M + H]⁺ A 6001

471.50 472.5[M + H]⁺ A 6002

594.61 595.7[M + H]⁺ B 6003

469.46 470.5[M + H]⁺ A 6004

454.45 455.5[M + H]⁺ A 6005

455.44 456.3[M + H]⁺ A 6006

455.44 456.3[M + H]⁺ A 6007

481.50 482.6[M + H]⁺ A 6008

467.47 468.5[M + H]⁺ A 6009

469.46 470.5[M + H]⁺ A 6010

469.46 470.5[M + H]⁺ A 6011

481.50 482.4[M + H]⁺ A 6012

481.50 482.4[M + H]⁺ A 6013

455.44 456.3[M + H]⁺ A 6014

473.52 474.5[M + H]⁺ A 6015

459.49 460.5[M + H]⁺ A 6016

503.89 504.9[M + H]⁺ A 6017

481.50 482.5[M + H]⁺ A 6018

469.49 470.5[M + H]⁺ A 6019

511.57 512.6[M + H]⁺ A 6020

473.52 474.5[M + H]⁺ A 6021

445.47 446.5[M + H]⁺ A 6022

497.54 498.6[M + H]⁺ A 6023

505.5 506.5[M + H]⁺ A 6024

459.49 460.6[M + H]⁺ A 6025

431.41 432.5[M + H]⁺ B 6026

355.31 356.4[M + H]⁺ A 6027

445.44 446.5[M + H]⁺ B 6028

431.41 432.4[M + H]⁺ B 6029

450.42 451.4[M + H]⁺ B 7000

487.4393 488.3[M + H]⁺ C 7001

503.5049 504.3[M + H]⁺ C 7002

487.4393 488.3[M + H]⁺ B 7003

464.4457 465.3[M + H]⁺ C 7004

526.5151 527.3[M + H]⁺ D 7005

481.4778 482.3[M + H]⁺ B 7006

502.5169 503.3[M + H]⁺ A 7007

502.5169 503.3[M + H]⁺ C 7008

481.5026 482.3[M + H]⁺ A 7009

481.5026 482.3[M + H]⁺ A 7010

509.5558 510.3[M + H]⁺ A 7011

521.5665 522.3[M + H]⁺ A 7012

521.5665 522.3[M + H]⁺ A 7013

535.5931 536.3[M + H]⁺ A 7014

535.5931 536.3[M + H]⁺ B 7015

509.5558 510.3[M + H]⁺ A 7016

523.5824 524.3[M + H]⁺ A 7017

523.5824 524.3[M + H]⁺ A 7018

481.4778 482.3[M + H]⁺ A 7019

495.5292 496.3[M + H]⁺ A 7020

495.5292 496.3[M + H]⁺ A 7021

466.233 468.3[M + H]⁺ A 7022

495.5292 496.3[M + H]⁺ A 7023

559.6145 560.3[M + H]⁺ B 7024

559.6145 560.3[M + H]⁺ A 7025

517.4835 518.3[M + H]⁺ A 7026

517.4835 518.3[M + H]⁺ A 8001

432.13 433.2[M + H]⁺ A 8002

518.14 519.3[M + H]⁺ A 8003

464.09 465.3[M + H]⁺ A 8004

482.14 483.3[M + H]⁺ A 8005

602.12 603.3[M + H]⁺ C 8006

520.15 521.3[M + H]⁺ B 8007

433.14 434.2[M + H]⁺ A 8008

340.1 341.2[M + H]⁺ B 8009

433.14 434.2[M + H]⁺ A 8010

421.14 422.2[M + H]⁺ A 8011

428.15 429.2[M + H]⁺ A 8012

428.15 429.2[M + H]⁺ A 8013

478.1 479.3[M + H]⁺ A 8014

369.11 370.2[M + H]⁺ A 8015

434.1 435.2[M + H]⁺ A 8016

428.15 429.2[M + H]⁺ A 8017

444.14 445.2[M + H]⁺ A 8018

417.14 418.2[M + H]⁺ A 8019

428.15 429.2[M + H]⁺ A 8020

414.13 415.2[M + H]⁺ A 8021

485.13 486.3[M + H]⁺ A 8022

442.16 443.2[M + H]⁺ A 8023

443.16 444.2[M + H]⁺ 8024

431.16 432.2[M + H]⁺ 8025

496.14 497.3[M + H]⁺ 8027

429.14 430.2[M + H]⁺ 2021F

437.1 438.1M + H]⁺ C 2023C

383.16 384.1[M + H]⁺ A 2024D

435.13 436.1[M + H]⁺ A 2022G

355.13 356.1[M + H]⁺ A 2025C

355.13 356.1[M + H]⁺ A 2028

407.1 408.1[M + H]⁺ A 2026H

449.1 450.1[M + H]⁺ A 2030A

375.08 376.1[M + H]⁺ C 2030C

400.13 401.2[M + H]⁺ C 2030B

426.15 427.1[M + H]⁺ B 2031C

387.10 388.1[M + H]⁺ A 2031D

441.11 442.0[M + H]⁺ A 2030D

477.16 478.1[M + H]⁺ B 2031A

463.13 464.0[M + H]⁺ B 2031B

373.09 374.0[M + H]⁺ B 2032B

382.11 383.1[M + H]⁺ B 2031E

431.13 432.1[M + H]⁺ B 2031F

417.11 418.1[M + H]⁺ BProcedures

EXAMPLE 4000

Compound 4000C was prepared from commercially available 4000A accordingto a published two-step procedure: Ebenbeck, W.; Rampf, F.; Marhold, A.PCT Intl. Appl. US 2004/0142820 A1 (Jul. 22, 2004). Compound 4000D wasprepared by procedures given in Examples 14, 1008, 9 and 1001. Compound4032 was prepared from Compound 4000D as described in Example 1004, butsubstituting Compound 4000C for 3-bromoimidazo[1,2-a]pyridine in Step 2.

EXAMPLE 4100

Compound 4100C was prepared from compound 4100A and commerciallyavailable Compound 4100B by procedures given in Example 14 and 1009.Subsequently, compound 4100C (123 mg, 0.2 mmol) was dissolved inmethanol (1 mL) in a pressure tube and treated with HCl (0.4 mL, 4 M indioxane). The tube was sealed and heated with stirring at 90° C. for 18h. The reaction mixture was allowed to cool to rt and the solvent wasthen removed under reduced pressure. The residue was re-dissolved inmethanol (1 mL) and DIPEA (0.27 mL, 0.20 mg, 1.6 mmol) was added. Thereaction mixture was stirred overnight at rt. The volatile componentswere removed by evaporation and the residue was purified by PTLC (8%MeOH—CH₂Cl₂) to give Compound 4017 (59 mg, 61% yield) as a beige solid.

EXAMPLE 1022

Step 1

To a solution of 1022A (500 mg, 3.33 mmol) in acetone (40 mL) were addedpotassium carbonate (920 mg, 6.7 mmol) and 1-bromo-2-butyne (0.32 mL,3.7 mmol, in case of R═CH₂CCCH₃). The reaction mixture was heated toreflux for 2 h. After cooling to RT, the mixture was added to icewater/CH₂Cl₂. The organic layers were extracted with CH₂Cl₂ and thecombined organic solution was washed with saturated aqueous NaClsolution, dried (Na₂SO₄), and concentrated in vacuo to afford 1022B (674mg, quantitative yield).

Steps 2 and 3

A suspension of 1022B (100 mg, 0.5 mmol) in 1N NaOH solution (0.5 mL)was heated to 100° C. The reaction mixture was stirred for 1 h at thetemperature and concentrated in vacuo. The residue was dried byazeotropic distillation with toluene and the resulting solid wasdissolved in DMF (0.6 mL) followed by addition of xs. MeI (0.1 mL, 1.5mmol). The mixture was stirred at RT for 2 h and diluted in EtOAc. Theorganic solution was washed with water, saturated aqueous NaCl solution,dried (Na₂SO₄), and concentrated in vacuo to give crude 1022C (117 mg).The crude 1022C (67 mg, 0.28 mmol) was dissolved in CH₂Cl₂ (2 mL) andthe solution was treated with PPh₃ (150 mg, 0.57 mmol) and CBr₄ (189 mg,0.57 mmol) at RT. The mixture was stirred at RT for 1 h and concentratedin vacuo. The residue was purified by preparative TLC (CH₂Cl₂) to afford1022D (50 mg, 60% yield).

Example 1023

Step 1

A mixture of 1023A (370 mg, 0.72 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(225 mg, 1.08 mmol), potassium carbonate (1M aqueous solution, 2.9 mL,2.9 mmol), and [PdCl₂(dppf)]CH₂Cl₂ (59 mg, 0.072 mmol) in acetonitrile(12 mL) was vacuumed and refilled with argon three times. The reactionmixture was stirred at 80° C. oil bath for 17 hours. After cooling down,the mixture was diluted in EtOAc (50 mL) and filtered through a celitepad. The filtrate was concentrated in vacuo and the residual materialwas purified by silica gel column chromatography (1% to 1.5% MeOH inCH₂Cl₂) to afford compound 1023B (369 mg, 99% yield).

Step 2

A solution of 1023B (109 mg, 0.21 mmol) in EtOAc/MeOH (4/1, 5 mL) wastreated with 4N HCl in dioxane (2 mL). The reaction mixture was stirredat RT for 15 h and concentrated in vacuo. The residue was dissolved inDMF (1 mL) and treated with 1022D (75 mg, 0.25 mmol, R═CH₂CCCH₃) anddiisopropylethyl amine (0.22 mL, 1.26 mmol). The mixture was stirred at60° C. for 9.5 h and concentrated in vacuo. The residue was dissolved inMeOH (5 mL) and treated with 4N HCl in dioxane (1 mL) at 70° C. for 17 hin a pressure vessel. After cooling to RT, the mixture was concentratedand the residue was treated with ammonia in MeOH for 0.5 h. Theprecipitate was filtered off and the filtrate was concentrated. Theresidue was dissolved in DMF (3-4 mL) and purified by reverse phasecolumn chromatography (0.01% HCO₂H in water-0.01% HCO₂H in acetonitrile)to afford 6018 (48 mg, 49% yield).

Example 1024

Step 1

A mixture of 1024A (811 mg, 2.8 mmol) and sodium diformyl amide (291 mg,3.0 mmol) in acetonitrile (15 mL) was stirred at RT for 19 h. Theresulting suspension was filtered through celite and the filtrate wasconcentrated in vacuo. The residue was purified by SiO₂ columnchromatography (CH₂Cl₂) to give 1024B (611 mg, 77% yield).

Step 2

A solution of 1024B (611 mg, 2.16 mmol) in EtOH (40 mL) was treated with4N HCl in dioxane (8 mL) at RT. The resulting solution was stirred at RTfor 16 h and concentrated in vacuo. The residue was dissolved indioxane/water (5/1, 24 mL) and the solution was stirred at RT for 2 h.The mixture was added to water and the organic layers were extractedwith CH₂Cl₂ and the combined organic solution was washed with saturatedaqueous NaCl solution, dried (Na₂SO₄), and concentrated in vacuo. Theresidue was purified by SiO₂ column chromatography (CH₂Cl₂/hexane=1/1 toCH₂Cl₂ only) to give 1024C (679 mg, 96% yield).

Example 1025

Step 1

A mixture of 1025A (52 mg, 0.11 mmol), benzyl bromide (13 □L, 0.11mmol), and cesium carbonate (108 mg, 0.33 mmol) in DMF (0.5 mL) wasstirred at RT for 2 h. The mixture was diluted in EtOAc and the organicsolution was washed with water, saturated aqueous NaCl solution, dried(Na₂SO₄), and concentrated in vacuo. The residue was purified bypreparative TLC (5% MeOH in CH₂Cl₂) to give 6027 (34 mg, 54% yield).

Example 1026

Step 1

To a solution of 1026A (41 mg, 0.084 mmol),5-hydroxymethyl-4-methyl-1,3-oxazole (19 mg, 0.17 mmol), and PPh₃ (66mg, 0.25 mmol) in THF (1 mL) was added diisopropy azodicarboxylate (50□L, 0.25 mmol) dropwisely at 0° C. The mixture was stirred at 0° C. for10 min and was allowed to warm to RT. After stirring for 2 h at RT, themixture was concentrated in vacuo and the residue was purified bypreparative TLC (CH₂Cl₂) to afford 1026B (38 mg, 77% yield).

Example 5021

Compound 5021 A was prepared using chemistry described in Examples 14,1001, and 1008.

Step 1

Compound 5021A was resolved by Chiralcel OD column (Mobile phase:Hexane:2-propanol 4:1). The first peak was collected and concentrated togive compound 5021B.

Step 2

Compound 5021B (1.82 g, 3.25 mmol), bis(pinacolato)diboron (2.89 g, 11.4mmol), potassium acetate (1.5 g, 15 mmol), and [PdCl₂(dppf)]CH₂Cl₂ (0.27g, 0.3 mmol) were added to a roundbottomed flask and placed under N₂.The flask was cycled three times between vacuum and nitrogen. Dioxane(30 mL, Aldrich anhydrous) was added via syringe. The reaction mixturewas stirred at 80° C. (oil bath) for 4 hours. The reaction mixture wasallowed to cool to rt. Water (30 mL) was added, followed by sodiumperborate-(5.0 g, 32 mmol). The reaction mixture was left stirringovernight at room temperature. The resulting mixture was diluted withEtOAc, washed with water and brine, dried with MgSO₄, and concentratedto dryness. The crude product was purified via flash silica gelchromatography using a 30% to 100% EtOAc-Hexanes gradient as the mobilephase. A white solid (1.28 g) was collected as product 5021C.

Step 3

Compound 5021C (40 mg, 0.12 mmol), cesium carbonate (59 mg, 1.5 eq), andDMF (1 mL) were added to a round bottomed flask. The flask was sonicatedfor 30 min. 2-bromopropane (18 mg, 1.2 eq) was added and the reactionmixture was stirred at rt overnight. The resulting mixture was dilutedwith EtOAc, washed with water, dried with MgSO₄, and concentrated todryness. The crude product was purified via flash chromatography using a10% to 100% EtOAc-Hexanes gradient as the mobile phase. Compound 5021D(28 mg) was obtained as product.

Step 4

Compound 5021 D was converted to compound 5021 using procedures similarto those described in Example 1001.

Example 7000

7025 was synthesized from 7031 using appropriate heterocyclic bromideusing the procedure similar to synthesis of 169.

7031 was prepared from 7030 using the procedure described below:

7030 (0.273 g, 0.5 mmol) in 5 mL anhydrous DMF was treated withpotassium carbonate (0.2 g, 0.15 mmol). The flask was equipped with adry ice acetone trap and difluoro choro methane gas was bubbled for 2 h.The bubbling was stopped and excess reagent was removed by bubblingnitrogen. The reaction was diluted with 50 mL ethyl acetate and washedwith water (2×50 mL) and brine (1×25 mL). The organics were dried andconcentrated to yield a crude which was purified by silica-gel prepplate chromatography using 1:1 ethyl acetate:hexane to yield 0.0 37 g ofpure product.

7030 itself was prepared from 214, using standard procedure reportedpreviously in this case.

Example 8001

Compound 8001B was prepared according to a literature procedure(Munyemana, F.; Frisque-Hesbain, A.; Devos, A.; and Ghosez, L.Tetrahedron Letters 30(23), 3077-3080, 1989).

Example 8002

Compound 8002A (746 mg, 1.32 mmol) was dissolved in anhydrousacetonitrile (10 mL) and the solution was colled to 0° C. by ice waterbath. BF₃-Et₂O (0.84 mL, 6.62 mmol) was added dropwise via syringe. Thesolution was stirred at 0° C. for two hours. DIPEA (1 mL) was addedfollowed by NaOH (1N, 1 mL). The solution was stirred at 25° C. for twohours. The solvent was removed and the product was purified by C18reverse phase chromatography (CH₃CN/water, 5% to 90%, with 0.5% HCO₂H)to give 8009. 8009 was dissolved in methanol and NaOH (1N, 1.0 mL, 1.0mmol, 0.95 equivalent) was added. The solution was stirred at 25° C. for30 minutes. The solvent was removed to give the sodium salt form of 8009(495 mg).

Example 2021

Step 1:

To a solution of compound 2021A (4 g, 26.8 mmol) in water (25 mL) andconcentrated sulfuric acid (1 mL) was added sodium nitrite (2.2 g, 31.8mmol) in water (10 mL) with ice bath cooling. The reaction mixture wasdiluted with concentrated sulfuric acid (20 mL). The reaction mixturewas added to 50% sulfuric acid (50 mL) at reflux and boiled for 2minutes. The reaction mixture was cooled to room temperature and dilutedwith water (250 mL). The mixture was extracted with diethyl ether (5×100mL). The combined organic layers were washed with sodium bicarbonatesolution and brine, dried over sodium sulfate and concentrated to afford2021B (1.6 g) as a yellow solid.

Step 2:

A mixture of compound 2021B (790 mg, 5.3 mmol), cesium carbonate (1.90g, 5.8 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.47 g,6.3 mmol) in NMP (15 mL) was stirred overnight at room temperature. Thereaction mixture was filtered and the solids were washed with ethylacetate. The filtrate was poured into water and extracted with ethylacetate. The combined organic layers were dried over sodium sulfate andconcentrated. Recrystallization from 30% ethyl acetate/hexane afford2021C (728 mg) as a yellow solid. HPLC-MS t_(R)=1.54 min (UV_(254 nm));mass calculated for formula C10H7F3O3 232.03, observed LCMS m/z 233.1(M+H).

Step 3:

A suspension of 2021C (168 mg, 0.72 mmol) and 1.0 N sodium hydroxide(0.72 mL, 0.72 mmol) in water (0.8 mL) was heated at 100° C. for 1 hour.The reaction mixture was concentrated and the residue was azeotropedwith toluene. The sodium salt was dissolved in DMF (1 mL) and methyliodide (0.135 mL, 2.16 mmol) was added. The reaction mixture was stirredfor 2 hours at room temperature. The reaction mixture was diluted withethyl acetate and water. The layers were separated and the aqueous layerwas extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over sodium sulfate and concentrated.Purification by chromatography (SiO₂, 30% ethyl acetate/hexane) afforded2021D (149 mg) as a solid. HPLC-MS t_(R)=1.56 min (UV_(254 nm)); masscalculated for formula C11H11F3O4 264.06, observed LCMS m/z 287.1(M+Na).

Step 4:

A mixture of 2021D (149 mg, 0.56 mmol), carbon tetrabromide (371 mg,1.12 mg), and triphenylphosphine (294 mg, 1.12 mmol) in dichloromethane(5 mL) was stirred for 40 minutes at room temperature. The mixture wasconcentrated and purified by chromatography (SiO₂, 5% to 10% ethylacetate/hexane) to afford 2021E (153) mg as an oil. HPLC-MS t_(R)=2.04min (UV_(254 nm)); mass calculated for formula C11H10BrF3O3 325.98,observed LCMS m/z 349 (M+Na).

Step 5:

Compound 2021F (136 mg) was prepared from 2021 E (151 mg, 0.46 mmol) and2D (118 mg, 0.45 mmol) using previously described procedures. HPLC-MSt_(R)=1.60 min (UV_(254 nm)); mass calculated for formula C20H15F4N3O4437.1, observed LCMS m/z 438.1 (M+Na).

Example 2022

Step 1:

Compound 2022C was prepared according to a modification of a procedureby Felding, J. et al. (J. Org. Chem. 1999, 64, 4196-4198) using4-Iodo-1-methyl-1H-pyrazole 2022A and Weinreb amide 2022B as startingmaterials. The crude reaction mixture was chromatographed (SiO₂, 60%-80%ethyl acetate/hexane) to give compound 2022C (62%). HPLC-MS t_(R)=1.18min (UV_(254 nm)); mass calculated for formula C11H17N3O3 239.1,observed LCMS m/z 184.1 (M−tBu+H).

Step 2:

BOCamino hydantoin 2022D was prepared using procedures described inExample 1, Step 2. (81%) HPLC-MS t_(R)=0.94 min (UV_(254 nm)); masscalculated for formula C13H19N5O4 309.1, observed LCMS m/z 310.1 (M+H).

Step 3:

Amino hydantoin 2022E was prepared using procedures described in Example1, Step 3. HPLC-MS t_(R)=0.18 min (UV_(254 nm)); mass calculated forformula C8H11N5O2 209.1, observed LCMS m/z 210.1 (M+H).

Step 4:

Hydantoin 2022G was prepared using procedures described in Example 8.HPLC-MS t_(R)=2.23 min (UV_(254 nm); 10 min); mass calculated forformula C17H17N5O4 355.1, observed LCMS m/z 356.1 (M+H).

Example 2023

Step 1:

To a slurry of sodium hydride (95%, 0.58 g, 23 mmol) in DMF (20 mL) wasadded a solution of 4-Iodo-1H-pyrazole (2023A) (4.07 g, 21 mmol) in DMF(20 mL) and the resulting mixture was stirred at rt for 10 min. Then2-iodopropane (2.52 mL, 25.2 mmol) was added dropwise and the resultingmixture was stirred at rt overnight. The reaction mixture wasconcentrated, diluted with ethyl acetate, washed with water (4 times),brine, dried and concentrated to give an oily residue which waschromatographed (SiO₂, 10%-20% ethyl acetate/hexane) to give4-Iodo-1-isopropyl-1H-pyrazole 2023B (3.27 g, 66%). HPLC-MS t_(R)=1.66min (UV_(254 nm)); mass calculated for formula C6H9IN2 235.98, observedLCMS m/z 237.0 (M+H).

Example 2024

Step 1:

Compound 2024B was prepared according to a modification of a procedureby Roppe, J. et al. (J. Med. Chem. 2004, 47, 4645-4648) using4-fluorophenylhydrazine hydrochloride 2024A andmalondialdehyde-bis-(dimethylacetal) as starting materials (95% yield).HPLC-MS t_(R)=1.62 min (UV_(254 nm)); mass calculated for formulaC9H7FN2 162.1, observed LCMS m/z 163.1 (M+H).

Step 2:

Compound 2024C was prepared according to a modification of a procedureby Rodriguez-Franco, M. I. et al. (Tetrahedron. Lett. 2001, 42, 863-865)(85% yield). HPLC-MS t_(R)=1.98 min (UV_(254 nm)); mass calculated forformula C9H6FIN2 287.96, observed LCMS m/z 288.9 (M+H).

Example 2025

Step 1:

Compound 2025B was prepared according to a modification of a procedureby Evans, D. A. et al. (J. Am. Chem. Soc. 2005, 127, 8942-8943) using1-Methyl-1H-imidazole 2025A and Weinreb amide 2022B as startingmaterials (42%). HPLC-MS t_(R)=1.24 min (UV_(254 nm)); mass calculatedfor formula C11H17N3O3 239.1, observed LCMS m/z 240.1 (M+H).

The following compounds were prepared using procedures described inExamples 2021 to 2025.

Compound Exact MS m/e # Structure mass (M + H) 2021F

437.1 438.1 2023C

383.16 384.1 2024D

435.13 436.1 2022G

355.13 356.1 2025C

355.13 356.1

Example 2026

Part A

To a solution of methyl 4-acetylbenzoate (2026A) (1.9 g, 10.6 mmol) inacetic acid (10 mL) was added dropwise bromine (1.7 g, 21.3 mmol). Themixture was heated at 60° C. for 30 min, then stirred at roomtemperature for 1 hour, and poured into cold water (30 mL). The lightyellow precipitate was collected, washed with water and dried (2.6 g,96%).

Part B

Compound 2026C was prepared from compound 2026B following the proceduredescribed in Example 1005.

Part C

Compound 2026D was prepared following the procedures described inExample 1: HPLC-MS t_(R)=1.36 min (UV_(254 nm)); mass calculated forformula C17H21N3O6 363.1, observed LCMS m/z 386.0 (M+Na).

Part D

To a mixture of 2026D (7.87 g, 21.7 mmol) and diisopropylethylamine (7.5mL, 43.4 mmol) in DMF (80 mL) was added 2-trimethylsilylethoxy methylchloride (4.7 mL, 23.8 mmol). The mixture was stirred at roomtemperature overnight, diluted with water and extracted with ethylacetate. The combined organic layers were washed with water, brine,dried over sodium sulfate and concentrated. The residue was purified bycolumn chromatography (SiO₂, 15% EtOAc/hexane to 30% EtOAc/hexane) toafford 2026E as a white solid (10.2 g, 95%): HPLC-MS t_(R)=2.17 min(UV_(254 nm)); mass calculated for formula C23H35N3O7Si 493.2, observedLCMS m/z 516.1 (M+Na).

Part E

Compound 2026F was prepared from ester 2026E following a procedure asdescribed in Guo, Z. et. al (WO 2005/121130A2).

Part F

Compound 2026G was prepared following a previously described procedure.HPLC-MS t_(R)=1.67 min (UV_(254 nm)); mass calculated for formulaC28H33N5O5SSi 579.2, observed LCMS m/z 580.3 (M+H).

Part G

Compound 2026G (65 mg, 0.11 mmol) was heated in a sealed tube in MeOH (2mL) and 4 N HCl in 1,4-dioxane (2 mL) overnight at 90° C. Solvent wasevaporated and the residue was stirred in MeOH (2 mL) and triethylamine(2 mL) at room temperature for 4 hours. The solvent was removed and theresidue was purified by reverse phase chromatography to give 2026H (11mg, 20%): HPLC-MS t_(R)=1.00 min (UV_(254 nm)); mass calculated forformula C22H19N5O4S 449.1, observed LCMS m/z 450.1 (M+H).

Compound Exact MS m/e # Structure mass (M + H) 2026H

449.1 450.1

Example 2030

Part A:

Compound 2030A was prepared using previously described methods from 2D.HPLC-MS t_(R)=3.80 min (UV_(254 nm)), Mass calculated for formulaC₁₈H₁₂F₃N₃O₃ 375.1, observed LCMS m/z 376.1 (M+H).

Part B:

Compound 2030A (100 mg, 0.27 mmol) and cyclopropylmethylamine (0.140 mL)in NMP (0.5 mL) was heated at 100° C. for 12 h. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc, washed withwater and brine, dried over Na₂SO₄, and concentrated. Recrystallizationfrom EtOAc/hexane yielded 2030B as a white solid (75 mg, 66%). HPLC-MSt_(R)=4.06 min (UV_(254 nm)), Mass calculated for formula C₂₂H₂₀F₂N₄O₃426.2, observed LCMS m/z 427.1 (M+H).

Example 2031

Part A:

Compound 2030B (250 mg, 0.67 mmol) in 1 mL of benzyl alcohol was addedwith powdered KOH (75 mg, 1.33 mmol). The reaction mixture was stirredat 100° C. for 2 h and cooled to room temperature. It was diluted withEtOAc, washed with 1N HCl, H₂O, and brine, dried over Na₂SO₄, andconcentrated. Flash column chromatography with EtOAc afforded 2031A as awhite solid (280 mg, 91%). HPLC-MS t_(R)=4.29 min (UV_(254 nm)), Masscalculated for formula C₂₅H₁₉F₂N₃O₄ 463.1, observed LCMS m/z 464.0(M+H).

Part B:

Compound 2031A (250 mg, 0.54 mmol) in EtOH (30 mL) was added with 10%palladium on carbon (100 mg). The reaction mixture was stirred at roomtemperature for 2 h under 1 atmosphere of hydrogen. It was then filteredthrough celite, washed with EtOH, and concentrated, affording 2031B as awhite solid (120 mg, 60%). HPLC-MS t_(R)=2.66 min (UV_(254 nm)), Masscalculated for formula C₁₈H₁₃F₂N₃O₄ 373.1, observed LCMS m/z 374.0(M+H).

Example 2032

Part A:

Compound 2032A was prepared using previously described method from 2D.HPLC-MS t_(R)=2.94 min (UV_(254 nm)), Mass calculated for formulaC₁₉H₁₃FN₄O₃ 364.1, observed LCMS m/z 365.0 (M+H).

Part B:

Compound 2032A (100 mg, 0.27 mmol) was dissolved in 2 mL of 90% H₂SO₄.After stirring at 60° C. for 10 h, the reaction mixture was poured into50 g of ice, and white solid was precipitated. Filtration and dryingunder vacuum gave 2032B as a white solid (80 mg, 78%). HPLC-MSt_(R)=2.01 min (UV_(254 nm)), Mass calculated for formula C₁₉H₁₅FN₄O₆382.1, observed LCMS m/z383.1 (M+H).

The following compounds were prepared as described in Examples 2030 to2032.

Compound Exact MS m/e # Structure mass (M + H) 2030A

375.08 376.1 2030C

400.13 401.2 2030B

426.15 427.1 2031C

387.10 388.1 2031D

441.11 442.0 2030D

477.16 478.1 2031A

463.13 464.0 2031B

373.09 374.0 2032B

382.11 383.1 2031E

431.13 432.1 2031F

417.11 418.1

Specific TACE inhibitory activity (Ki values) of some representativecompounds of the present invention described above is set forth below:

Exact Mass Compounds Structures Mass Obsvd Ki (nM) 8009

433.14 434.2[M + H]⁺ 0.79 3009

478.16 479.3[M + H]⁺ 1.47 3010

492.20 493.3[M + H]⁺ 5 8011

428.15 429.2[M + H]⁺ 0.64 8012

428.15 429.2[M + H]⁺ 0.8 7011

521.5665 522.3[M + H]⁺ 2.24 7012

521.5665 522.3[M + H]⁺ 2.75 8015

434.1 435.2[M + H]⁺ 0.63 7016

523.5824 524.3[M + H]⁺ 3.08 7017

523.5824 524.3[M + H]⁺ 3.79 4013

429.2 430.2[M + H]⁺ 1.2nM 7018

481.4778 482.3[M + H]⁺ 3.25 8016

428.15 429.2[M + H]⁺ 0.48 8019

428.15 429.2[M + H]⁺ 1 5006

471.2 472.1[M + H]⁺ 0.5 7020

495.5292 496.3[M + H]⁺ 2.85 4025

458.2 459.3[M + H]⁺ 0.84nM 5019

367.12 368.2[M + H]⁺ 2 5010

405.1 406.2[M + H]⁺ 0.2 3041

513.20 514.3[M + H]⁺ 1.44 4012

467.2 468.3[M + H]⁺ 0.5nM

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications that are within the spirit and scopeof the invention, as defined by the appended claims.

1. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, ester, or isomerthereof.
 2. The compound of claim 1, selected from the group consistingof:

or a pharmaceutically acceptable salt, solvate, ester or isomer thereof.3. A pharmaceutical composition comprising at least one compound ofclaim 1, or a pharmaceutically acceptable salt, solvate, ester or isomerthereof, and at least one pharmaceutically acceptable carrier.